Resolution of alpha-(phenoxy) phenylacetic acid derivatives

ABSTRACT

The present invention provides a method for producing an enantiomerically enriched α-(phenoxy)phenylactic acid compound of the formula:  
                 
 
from its enantiomeric mixture, where R 1  is alkyl or haloalkyl and X is halide.

FIELD OF THE INVENTION

The present invention relates to an enantioselective resolution processfor the separation of α-(phenoxy)phenylactic acids from its enantiomericmixture.

BACKGROUND OF THE INVENTION

Esters and amides derivatives of α-(phenoxy)phenylactic acids, such ashalofenate, are chiral compounds and are useful in ameliorating avariety of physiological conditions, including conditions associatedwith blood lipid deposition, e.g., Type II diabetes and hyperlipidema.See, for example, U.S. Pat. Nos. 3,517,050 and 6,262,118.α-(phenoxy)phenylactic acids contain a single chiral center at anasymmetrically substituted carbon atom alpha to the carbonyl carbonatom, and therefore exist in two enantiomeric forms.

Cytochrome P450 2C9 is an enzyme known to play a significant role in themetabolism of specific drugs. It is known to one skilled in the art thatchanges in drug metabolism mediated by inhibition of cytochrome P450enzymes has a high potential to precipitate significant adverse effectsin patients. It is also known that a racemic α-(phenoxy)phenylacticacid, e.g., halofenic acid, inhibits cytochrome P450 2C9. See, forexample, U.S. Pat. No. 6,262,118. Thus, administration of a racemicα-(phenoxy)phenyl-acetic acid, such as halofenic acid or itsderivatives, can lead to a variety of drug interaction problems withother drugs, including anticoagulants, anti-inflammatory agents andother drugs that are metabolized by this enzyme. It has been found thatthe (−)-enantiomer of halofenic acid is about twenty-fold less active inits ability to inhibit cytochrome P450 2C9 compared to the(+)-enantiomer. Id. Thus, it is desirable to administer the(−)-enantiomer of halofenic acid or its derivatives which issubstantially free of the (+)-enantiomer to reduce the possibility ofdrug interactions.

Therefore, there is a need for an efficient process for producing aproduct enriched in a desired enantiomer of a α-(phenoxy)phenylacidicacid, e.g., (−)-halofenic acid.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a method for producing anenantiomerically enriched α-(phenoxy)phenylactic acid compound of theformula:

wherein

-   -   R¹ is alkyl or haloalkyl, and    -   X is halide;        from an enantiomeric mixture of the α-(phenoxy)phenylactic acid        compound comprising a first and a second enantiomers. In one        particular embodiment, the enantiomeric mixture is a racemic        mixture.

Methods of the present invention includes:

-   -   (a) producing a solution comprising a solid enantiomerically        enriched acid-base salt of the first enantiomer by contacting        the enantiomeric mixture of the α-(phenoxy)phenylactic acid        compound with less than 0.5 molar equivalents of an        enantiomerically enriched chiral amine compound under conditions        sufficient to produce the ratio of the amount of free first        enantiomer to the amount of the free second enantiomer in the        solution is about 1 to 3; and    -   (b) separating the solid acid-base salt of the first enantiomer        from the solution at a temperature where the concentration of an        acid-base salt of the second enantiomer of the        α-(phenoxy)phenylactic acid compound is near or below its        saturation point.

At least a portion of the second enantiomer can be converted to thefirst enantiomer, e.g., racemized, by contacting the second enantiomerwith a base. The resulting enantiomeric mixture can then be recycled andsubjected to a similar enantiomeric enrichment process to increase theyield of the first enantiomer acid-base salt.

In one particular embodiment, the chiral amine compound is of theformula:

wherein

-   -   each of R² and R³ is independently hydrogen or alkyl; or R² and        R³ together with atoms to which they are attached to form a        heterocyclic ring moiety;    -   R⁴ is hydrogen or alkyl;    -   each of R⁵ and R⁶ is independently hydrogen or alkyl, or one of        R⁵ or R⁶ is an amine protecting group; and    -   Ar is aryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the solubility profiles of (−)- and(+)-CPTA/CAF D-Base salts in 2-propanol.

FIG. 2 shows results of a process for resolving a racemic mixture ofCPTA using CAF D-Base under a variety of crystallization conditions.

FIG. 3 is a graph showing the solubility of (−)- and (+)-CPTA/CAF D-Basesalts in pure isopropanol and a solution comprising a mixture ofisopropanol and CPTA (11%).

FIG. 4 is a graph showing the composition of a mixture with a variousamount of each components.

FIG. 5 is a graph showing a (−/+)-salt saturation profile forcrystallization and heating.

FIG. 6 is a table showing comparison of the model prediction toexperimental results for entry 4 of FIG. 2.

FIG. 7 is a graph showing the amount of (+)-salt formation as a functionof the amount of CAF D-Base added.

FIG. 8 is a graphic representation of experimental data for theresolution shown in entry 11 of FIG. 2.

FIG. 9 shows the actual and calculated amount of CPTA in mother liquorand a graphic comparison of a calculated percentage of (+)-CPTA saltwith the experimental data.

FIG. 10A shows tables showing experimental data and a solubility modelcalculation for FIG. 7 (i.e., entry 13 of FIG. 2).

FIG. 10B is a table showing experimental data and a solubility modelcalculation for entry 4 of FIG. 2 at 28.3° C.

FIG. 11 is a graph showing solubility of racemic CPTA at varioustemperatures in 1,2-dichloroethane.

FIG. 12 is a graph showing solubility of racemic CPTA at varioustemperatures in heptane.

FIG. 13 is a table of results in Example 24 showing yield of CPTAresolution using CAF D-Base under variety of crystallization conditions.

FIG. 14 shows a cooling profiles for the resolution crystallization ofvarious entries in FIG. 2.

FIG. 15 is a table showing the amount of (−)-halofenate yield from(−)-CPTA salt in Example 26.

FIG. 16 is a graph showing solubility of racemic CPTA sodium salt atvarious temperatures in water.

FIG. 17 is a graph showing CPTA racemization profile at various pHduring hydrolysis of (−)-halofenate.

FIG. 18 is a table showing the results of CAF D-Base recovery at variouspH as described in Example 30.

FIG. 19 is experimental results of solubility determination of racemicCPTA in 1,2-dichloroethane and heptane as determined in Example 33.

FIG. 20 is experimental results of solubility determination of racemicCPTA sodium salt in water as determined in Example 41.

FIG. 21 is experimental results of basic hydrolysis of (+)-halofenate asdetermined in Example 42.

DETAILED DESCRIPTION

I. Definitions

“Alkyl” refers to straight or branched aliphatic hydrocarbons chaingroups of one to ten carbon atoms, preferably one to six carbon atoms,and more preferably one to four carbon atoms. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, 2-propyl,tert-butyl, pentyl, and the like.

“Aryl” refers to a monovalent monocyclic or bicyclic aromatichydrocarbon moiety of 6 to 10 carbon ring atoms. Unless stated orindicated otherwise, an aryl group can be substituted with one or moresubstitutents, preferably one, two, or three substitutents, and morepreferably one or two substitutents selected from alkyl, haloalkyl,nitro, and halo. More specifically the term aryl includes, but is notlimited to, phenyl, 1-naphthyl, and 2-naphthyl, and the like, each ofwhich is optionally substituted with one or more substitutent(s)discussed above.

“CAF D base” refers to chloramphenicol D base, i.e.,D-threo-(−)-2-amino-1-(nitrophenyl)-1,3-propanediol.

“Chiral” or “chiral center” refers to a carbon atom having fourdifferent substitutents. However, the ultimate criterion of chirality isnon-superimposability of mirror images.

The terms “CPTA” and “halofenic acid” are used interchangeably hereinand refer to (4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid.

“Enantiomeric mixture” means a chiral compound having a mixture ofenantiomers, including a racemic mixture. Preferably, enantiomericmixture refers to a chiral compound having a substantially equal amountsof each enantiomers. More preferably, enantiomeric mixture refers to aracemic mixture where each enantiomer is present in an equal amount.

“Enantiomerically enriched” refers to a composition where one enantiomeris present in a higher amount than prior to being subjected to aseparation process.

“Enantiomeric excess” or “% ee” refers to the amount of differencebetween the first enantiomer and the second enantiomer. Enantiomericexcess is defined by the equation: % ee=(% of the first enantiomer)−(%of the second enantiomer). Thus, if a composition comprises 98% of thefirst enantiomer and 2% of the second enantiomer, the enantiomericexcess of the first enantiomer is 98%-2% or 96%.

The terms “halide” and “halo” are used interchangeably herein and referto halogen, which includes F, Cl, Br, and I, as well as pseudohalides,such as —CN and —SCN.

“Haloalkyl” refers to alkyl group as defined herein in which one or morehydrogen atoms have been replaced with halogens, includingperhaloalkyls, such as trifluoromethyl.

“Halofenate” refers to 2-acetamidoethyl4-chlorophenyl-(3-trifluoromethyl-phenoxy)acetate (i.e.,4-chloro-α-(3-(trifluoromethyl)phenoxy)benzeneacetic acid,2-(acetylamino)ethyl ester or(4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid),2-(acetylamino)ethyl ester).

“Heteroalkyl” means a branched or unbranched acyclic saturated alkylmoiety containing one or more heteroatoms or one or moreheteroatom-containing substitutents, where the heteroatom is O, N, or S.Exemplary heteroatom-containing substitutents include ═O, —OR^(a),—C(═O)R^(a), —NR^(a)R^(b), —N(R^(a))C(═O)R^(b), —C(═O)NR^(a)R^(b) and—S(O)_(n)R^(a) (where n is an integer from 0 to 2). Each of R^(a) andR^(b) is independently hydrogen, alkyl, haloalkyl, aryl, or aralkyl.Representative examples of heteroalkyl include, for example, N-acetyl2-aminoethyl (i.e., —CH₂CH₂NHC(═O)CH₃).

The terms “heterocyclyl” and “heterocyclic ring” are usedinterchangeably and refer to a non-aromatic cyclic moiety of 3 to 8 ringatoms in which one, two, or three ring atoms are heteroatoms selectedfrom N, O, or S(O)_(n) (where n is an integer from 0 to 2), theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl group. Unless stated or indicated otherwise, theheterocyclyl ring can be optionally substituted independently with one,two, or three substitutents selected from halogen, alkyl, aryl, hydroxy,amino, or alkoxy. More specifically the term heterocyclyl includes, butis not limited to, 1,3-dioxane and its derivatives, and the like.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo, andiodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.,acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

The term “metal” includes Group I, II, and transition metals as well asmain group metals, such as B and Si.

“Optical purity” refers to the amount of a particular enantiomer presentin the composition. For example, if a composition comprises 98% of thefirst enantiomer and 2% of the second enantiomer, the optical purity ofthe first enantiomer is 98%.

Unless otherwise stated, the term “phenyl” refers to an optionallysubstituted phenyl group. Suitable phenyl substitutents are same asthose described in the definition of “aryl.”Similarly, the term“phenoxy” refers to a moiety of the formula —OAr^(a), wherein Ar^(a) isphenyl as defined herein. Thus, the term “α-(phenoxy)phenylactic acid”refers to acetic acid that is substituted on the 2-position with anoptionally substituted phenyl and optionally substituted phenoxymoieties.

“Protecting group” refers to a moiety that when attached to a reactivegroup in a molecule masks, reduces or prevents that reactivity. Examplesof protecting groups can be found in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley &Sons, New York, 1999, and Harrison and Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996),which are incorporated herein by reference in their entirety.Representative hydroxy protecting groups include acyl groups, benzyl andtrityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allylethers. Representative amino protecting groups include, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC),and the like.

The term “rate” when referring to a formation of a salt refers tokinetic and/or thermodynamic rates.

As used herein, the term “treating”, “contacting” or “reacting” refersto adding or mixing two or more reagents under appropriate conditions toproduce the indicated and/or the desired product. It should beappreciated that the reaction which produces the indicated and/or thedesired product may not necessarily result directly from the combinationof two reagents which were initially added, i.e., there may be one ormore intermediates which are produced in the mixture which ultimatelyleads to the formation of the indicated and/or the desired product.

As used herein, the terms “those defined above” and “those definedherein” when referring to a variable incorporates by reference the broaddefinition of the variable as well as preferred, more preferred and mostpreferred definitions, if any.

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes R and S are used to denotethe absolute configuration of the molecule about its chiral center(s).The prefixes “d” and “1” or (+) and (−) are employed to designate thesign of rotation of plane-polarized light by the compound, with (−) or(1) meaning that the compound is “levorotatory” and with (+) or (d) ismeaning that the compound is “dextrorotatory”. There is no correlationbetween nomenclature for the absolute stereochemistry and for therotation of an enantiomer. For a given chemical structure, thesecompounds, called “stereoisomers,” are identical except that they aremirror images of one another. A specific stereoisomer can also bereferred to as an “enantiomer,” and a mixture of such isomers is oftencalled an “enantiomeric” or “racemic” mixture. See, e.g., Streitwiesser,A. & Heathcock, C. H., INTRODUCTION TO ORGANIC CHEMISTRY, 2^(nd)Edition, Chapter 7 (MacMillan Publishing Co., U.S.A. 1981).

The terms “substantially free of its (+)-stereoisomer,” “substantiallyfree of its (+)-enantiomer,” are used interchangeably herein and meanthat the compositions contain a substantially greater proportion of the(−)-isomer in relation to the (+)-isomer. In a preferred embodiment, theterm “substantially free of its (+) stereoisomer” means that thecomposition is at least 90% by weight of the (−)-isomer and 10% byweight or less of the (+)-isomer. In a more preferred embodiment, theterm “substantially free of its (+)-stereoisomer” means that thecomposition contains at least 99% by weight of the (−)-isomer and 1% byweight or less of the (+)-isomer. In the most preferred embodiment, theterm “substantially free of its (+)-stereoisomer” means that thecomposition contains greater than 99% by weight of the (−)-isomer. Thesepercentages are based upon the total amount of isomers in thecomposition.

II. Introduction

While chiral synthesis has made an extensive progress in recent years,resolution of racemates still remains the method of choice in industrialprocess for preparation of optically active, i.e., chiral, compounds.Typically, a chiral compound is synthesized in a racemic form and thefinal product is resolved to yield an enantiomerically enrichedcompound.

This process of resolving the final product is particularly useful in alarge scale preparation of pharmaceutically active chiral compounds.Although enantiomers of a chiral compound have exact same chemicalbonds, the spatial orientation of atoms in enantiomers is different.Thus, one enantiomer of a chiral drug often exerts desired activity witha significantly less side-effect(s) than the other enantiomer. Whilesuch relationship between chirality of an optically active drug and itsside-effect(s) has been known for sometime, many chiral drugs are stilladministered in a racemic form.

Diastereomeric crystallization is widely used on industrial scale. Thetheoretical once-through yield of a resolution via diastereomercrystallization is 50 percent. Typically, however, more than onere-crystallization process is necessary in order to produce acomposition that is of a sufficient optical purity.

The present invention provides a method for enantiomerically enrichingan enantiomeric mixture, preferably a racemic mixture, ofα-(phenoxy)phenylactic acid compound, e.g., halofenic acid. Preferably,methods of the present invention provides a solid acid-base salt of the(−)-enantiomer of α-(phenoxy)phenylactic acid compound. In this manner,the (−)-enantiomer can be readily separated from the solution.

The carboxylic acid group of the enantiomerically enrichedα-(phenoxy)phenylactic acid can then be activated by a carboxylic acidactivation group to produce an activated α-(phenoxy)phenylactic acid,which can be reacted with an alcohol, an amine, a thiol, or othernucleophilic compounds to produce an enantiomerically enrichedα-(phenoxy)phenylactic acid esters, amides, thioesters, or otherderivatives, respectively. Thus, enantiomerically enrichedα-(phenoxy)phenylactic acid compounds produced using methods of thepresent invention are useful in producing α-(phenoxy)phenylactic acidderivatives such as those disclosed in U.S. Pat. No. 3,517,050. Inparticular, methods of the present invention are useful in producing(−)-halofenate.

III. Enantioselective Crystallization

As noted above, most enantioselective crystallization processes requiremore than one re-crystallization process in order to produce acomposition that is of a sufficient optical purity. However, presentinventors have found that under certain conditions disclosed herein,α-(phenoxy)phenylactic acid compound of a sufficient optical purity canbe produced by a single crystallization process. Thus, in one aspect,methods of the present invention are based on the surprising andunexpected discovery by the present inventors that an enantiomericmixture of a α-(phenoxy)phenylactic acid compound can beenantiomerically enriched using a chiral amine compound. In particular,methods of the present invention provide a desired enantiomer of theα-(phenoxy)phenylactic acid compound in optical purity of at least about90%, preferably at least about 95%, more preferably at least about 97%,and most preferably at least about 98%.

In one embodiment, methods of the present invention provide enantiomericenrichment of an enantiomeric mixture, preferably a racemic mixture, ofa α-(phenoxy)phenylactic acid compound of the formula:

wherein R¹ is alkyl or haloalkyl, and X is halide. The process generallyinvolves forming a solid enantiomerically enriched acid-base salt of theα-(phenoxy)phenylactic acid compound using a chiral amine compound.

In particular, methods of the present invention are directed to theresolution of α-(phenoxy)phenylacetate acid, e.g., halofenic acid (whereR¹ is CF₃ and X is C1), of the formula:

wherein R¹ is alkyl or haloalkyl, and X is halide.

In one particular embodiment, methods of the present invention aredirected to the resolution of α-(phenoxy)phenylacetate acid of Formula Ior, preferably of Formula II, where X is chloro.

Yet in another embodiment, methods of the present invention are directedto the resolution of α-(phenoxy)phenylactic acid of Formula I or,preferably, Formula II, where R¹ is haloalkyl, preferablytrifluoromethyl.

In one particular embodiment, α-(phenoxy)phenylactic acid iscrystallized using a chiral base. A wide variety of chiral bases can beused, including those disclosed in the Examples section below.Preferably, the chiral base used results in a solid acid-base salt ofthe (−)-enantiomer of α-(phenoxy)phenylactic acid. In this manner, the(−)-enantiomer is readily separated from the solution, for example, byfiltration. In one particular embodiment, the chiral base is an aminecompound of the formula:

wherein each of R² and R³ is independently hydrogen, alkyl or a hydroxyprotecting group; or R² and R³ together with atoms to which they areattached to form a heterocyclic ring moiety; R⁴ is hydrogen or alkyl;each of R⁵ and R⁶ is independently hydrogen or alkyl, or one of R⁵ or R⁶is an amine protecting group; and Ar is aryl.

In one particular embodiment, R² and R³ together along with oxygen atomsto which they are attached to form 1,3-dioxane, a substituted1,3-dioxane (e.g., dialkyl substituted 1,3-dioxane, such as5,5-dimethyl-1,3-dioxane), or a derivative thereof.

In another embodiment, R² and R³ are hydrogen.

Yet in another embodiment, R⁴ is hydrogen.

In still another embodiment, Ar is a substituted aryl. A particularlypreferred Ar moiety is optionally substituted phenyl. An especiallypreferred Ar moiety is 4-nitrophenyl.

Still further, combinations of the preferred groups described above willform other preferred embodiments. For example, one particularlypreferred chiral base is an amine compound of Formula III above, whereinR², R³, R⁴, R⁵ and R⁶ are hydrogen; and Ar is 4-nitrophenyl. And aparticularly preferred α-(phenoxy)phenylactic acid compound is ofFormula II above, wherein R¹ is trifluoromethyl and X is chloro. In thismanner, a wide variety of preferred chiral bases andα-(phenoxy)phenylactic acid compounds are embodied within the presentinvention.

The present inventors have found that the amount of chiral base used incrystallization of the α-(phenoxy)phenylactic acid has a significanteffect on the optical purity of the enantiomeric enrichment. Forexample, when a chiral amine compound of the formula:

(wherein R², R³, R⁴ and Ar are those defined herein) is used incrystallization of the α-(phenoxy)phenylactic acid compound, higher % eeobtained by using the chiral amine compound in an amount less than 0.5molar equivalent, preferably about 0.48 molar equivalent or less, morepreferably about 0.47 molar equivalent or less, and most preferablyabout 0.45 molar equivalent or less. It should be recognized that thechiral amine compound itself should be of a sufficient enantiomericpurity in order to yield a highly enantiomerically enrichedα-(phenoxy)phenylactic acid derivatives.

The crystallization is typically conducted in a solvent that allows adifferent solubility of salts that are formed between two enantiomers ofthe α-(phenoxy)phenylactic acid and the chiral amine. In this manner,one of the diastereomeric salt precipitates out of the solutionpreferentially. Suitable crystallization solvents include proticsolvents, such as alcohols. A particularly preferred crystallizationsolvent is isopropyl alcohol.

The yield of enantiomerically enriched α-(phenoxy)phenylactic acid alsodepends on, among others, the amount of crystallization solvent used.For example, if a large quantity of crystallization solvent is used, themixture becomes too dilute and the solid formation is reduced. If theamount of crystallization solvent used is too small, the solution willbe supersaturated with the undesired diastereomeric salt which may leadto crystallization of the undesired diastereomeric salt, therebyreducing the optical purity of a desired enantiomer. Thus, whenisopropanol is used as the crystallization solvent, the amount ofcrystallization solvent used is preferably from about 2 grams to about 6grams per one gram of the α-(phenoxy)phenylactic acid compound, morepreferably from about 3 grams to about 5 grams, still more preferablyfrom about 3.5 grams to about 4.5 grams, and most preferably about 4grams.

In one embodiment, the crystallization process involves heating thecrystallization solution mixture to a temperature above the nucleationtemperature of both enantiomers to dissolve substantially all of bothenantiomers. For example, the crystallization solution is heated to atemperature in the range of from about 60° C. to the boiling point ofthe solution, preferably from about 70° C. to about 80° C. Morepreferably, the crystallization solution is heated to about 75° C. Thesolution can be heated prior to and/or after the chiral amine compoundis added. Heating is carried out until the solid materials aresubstantially completely dissolved, which typically ranges from about0.5 to about 16 hours, preferably from about 1 to about 8 hours.

The crystallization solution is then cooled until it is at or below thenucleation temperature of the first diastereomeric salt, e.g., salt of(−)-enantiomer of the α-(phenoxy)-phenylactic acid, but preferably abovethe nucleation temperature of the second diastereomeric salt, e.g., saltof (+)-enantiomer of the α-(phenoxy)phenylactic acid. This allowsformation of a solid acid-base salt of the first enantiomer with thechiral amine compound. Without being bound by any theory, it is believedthat the use of a chiral amine compound results in formation of anacid-base salt with one of the enantiomer at a significantly faster ratethan formation of an acid-base salt of the other enantiomer. This ratemay be due to kinetic and/or thermodynamic rate difference between thetwo enantiomers. As with a typical compound, the solubility profile ofthe α-(phenoxy)phenylactic acid compound of the present invention has ahigher solubility at a higher temperature. Therefore, by cooling thecrystallization solution to just above the nucleation temperature of thesecond diastereomeric salt affords a higher recovery yield of the solidfirst diastereomeric salt.

After the slurry is formed, the crystallization solution can be furthercooled until the temperature of the solution is near or above thesaturation point of the second diastereomeric salt. This preventsformation of a diastereomeric solid acid-base salt from the secondenantiomer while increasing the formation of the diastereomeric solidacid-base salt of the first enantiomer.

The rate of cooling the crystallization solution may affect the opticalpurity of the solid acid-base salt that is formed. For example, if thecrystallization solution is cooled too fast, the undesirable enantiomermay get trapped within the lattice of the solid acid-base salt of thedesired enantiomer. However, a too slow cooling rate increases theproduction time and cost. Therefore, the crystallization solution shouldbe cooled at a rate which minimizes the loss of optical impurity but ata rate sufficient to be economical. Typically, the crystallizationsolution cooling rate is from about 0.05° C./min to about 1° C./min,preferably from about 0.1° C./min to about 0.7° C./min, and morepreferably from about 0.25° C./min to about 0.4° C. The crystallizationsolution is then maintained at above the saturation point of the solidacid-base salt of the second, i.e., undesired, enantiomer. Typically,the crystallization solution is maintained at this temperature for about1 to about 72 hours, preferably from about 2 to about 48 hours, and morepreferably from about 3 to about 30 hours.

As expected, using a small amount of chiral amine compound allowsselective formation of the solid acid-base salt of the first enantiomer.However, the resulting yield will correspondingly be small.Theoretically, the amount of yield of the desired enantiomer from aracemic mixture is 50%. Thus, if 0.5 molar equivalent of the chiralamine compound is used, the theoretical yield is 50% of the totalα-(phenoxy)phenylactic acid (or 100% of the desired enantiomer). Inorder to be economically desirable, methods of the present inventionprovide at least about 50% yield of the desired enantiomer, preferablyat least about 60%, more preferably at least about 70%, and mostpreferably at least about 75%. Assuming 100% selectivity, these yieldscorrespond to adding about 0.25, 0.30, 0.35 and 0.375 molar equivalentof the chiral amine compound, which represent a minimum amount of thechiral amine compound that need to be added to the crystallizationsolution.

It is believed that the tendency for the second enantiomer to form asolid acid-base salt with the chiral amine compound is one of the majorcauses for variability of conventional crystallization processes. Thus,by determining the supersaturation point of the second, i.e., undesired,enantiomer, one can minimize or prevent unpredictability of a solidacid-base formation of the second enantiomer. Supersaturation points canbe readily determined by one skilled in the art, e.g., by a solubilityexperiment.

It should be noted that while methods of the present invention arediscussed in reference to the enrichment of (−)-enantiomer that ispresent in the racemic mixtures, methods of the present invention arealso applicable for enriching the (+)-enantiomer. The method of thepresent invention essentially provides a solid precipitate enriched inthe (−)-enantiomer and a liquid filtrate, i.e., mother liquor, enrichedin the (+)-enantiomer. Liberation of the desired (−)-enantiomer andrecovery of the chiral amine compound from the precipitated salt can bereadily accomplished by acidification of the salt with, for example, adilute mineral acid or any other inorganic or organic acidconventionally known to hydrolyze salts of this nature. While thisprocedure leaves the filtrate as an undesired by-product, the filtratecan be further treated with acid or, preferably, base to convert the(+)-enantiomer enriched filtrate to the racemic mixture. For example,the (+)-enantiomer can be racemized using aqueous sodium hydroxidesolution. This racemic mixture can then be reused, i.e., recycled. Inaddition, the chiral amine compound can also be recovered from the abovedescribed conversion step and recycled. Thus, the process of the presentinvention lends itself readily to a recycling-type of procedure.

IV. Synthesis of Racemic α-(phenoxy)phenylactic Acid

One method of producing a racemic mixture of α-(phenoxy)phenylactic acidof Formula I is shown in Scheme I below.

Thus, conversion of phenylactic acid 1 to an activated carboxylic acidderivative, e.g, acid chloride, followed by α-bromination gaveα-bromophenylacetyl chloride (not shown). The acid chloride was thenconverted to ester 2, where R is typically alkyl. Preferably, alcoholROH, which is used to convert the acid chloride to ester 2, is the samealcohol that is used as a solvent in a subsequent reaction. In thismanner, the number of different solvent types is minimized. In addition,by using the same ROH as the solvent in the subsequent reaction, theamount of by-product, e.g., by trans-esterification, formation isminimized. For example, isopropyl ester 2, i.e., where R is isopropyl,is particularly advantages as the subsequent reaction is convenientlycarried out in isopropanol solvent. A displacement reaction of ester 2with a phenol compound 3 in the presence of a base, such as a hydroxide(e.g., potassium hydroxide), gave a α-(phenoxy)phenylactic acid ester 4.Hydrolysis of α-(phenoxy)phenylactic acid ester 4 affordedα-(phenoxy)phenylactic acid I.

In this manner, (4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid,i.e., CPTA, can be prepared in five steps without intermediate isolationin about 85% yield following crystallization from heptane.

V. Utility of Enantiomerically Enriched α-(phenoxy)phenylactic Acid

Enantiomerically enriched α-(phenoxy)phenylactic acid compounds areuseful intermediates in preparing a variety of pharmaceutically activecompounds, including α-(phenoxy)phenylactic acid compounds disclosed inU.S. Pat. No. 3,517,050. Thus, anther aspect of the present inventionprovides a method for enantioselectively producing aα-(phenoxy)phenylacetate compound of the formula:

from a racemic mixture of a α-(phenoxy)phenylactic acid compound FormulaI, wherein R¹ is alkyl or haloalkyl, X is halide and R⁷ is heteroalkyl,preferably N-acetyl 2-aminoethyl (i.e., a moiety of the formula—CH₂CH₂NHC(═O)CH₃). The method involves resolving the racemic mixture ofthe α-(phenoxy)phenylactic acid compound of Formula I as described aboveand producing an enantiomerically enriched activatedα-(phenoxy)phenylactic acid by reacting the enantiomerically enrichedα-(phenoxy)phenylactic acid with a carboxylic acid activating reagent.Suitable carboxylic acid activating reagents include thionyl halides(e.g., thionyl chloride), anhydrides, thioester generating reagents, andother carboxylic acid activating reagents known to one skilled in theart.

The activated α-(phenoxy)phenylactic acid is than reacted with acompound of the formula (R⁷—O)_(w)M, e.g., N-acetyl ethanolaminederivative, to produce enantiomerically enrichedα-(phenoxy)phenylacetate compound of Formula III, where R⁷ is as definedabove, M is hydrogen or a metal, e.g., Na, K, Li, Ca, Mg, Cs, etc. andthe superscript w is the oxidation state of M. The present inventorshave discovered that the reaction between the activated acid and thecompound of formula (R⁷—O)_(w)M can be carried out without anysignificant racemization.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting.

EXAMPLES

Reagents and Experimental Setup

Unless otherwise stated, reagents and solvents were purchased fromAldrich Chemical or Fisher Scientific. N-Acetylethanolamine was alsoobtained from Lancaster Synthesis. The racemic CPTA, i.e., halofenicacid was prepared according to the procedures disclosed in U.S. Pat.Nos. 3,517,050 and 6,262,118 all of which are incorporated herein byreference in their entirety.(1R,2R)-(−)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol (i.e., CAF D-Base)was obtained from TCI Americas.

Operations were conducted under a positive nitrogen atmosphere. A Camileprocess control computer attached to a recirculating heating and coolingsystem was used to regulate jacket temperatures in the jacketedstraight-walled bottom-drain glass reactors. Unless otherwise indicated,solvents were removed using a Buchi rotary evaporator at 15 to 25 torrwith a bath temperature of up to 40° C. Solid samples were dried in avacuum oven at 40° C., 15 to 25 torr. A Cenco HYVAC vacuum pump was usedto supply vacuum of less than 1 torr for vacuum distillations. Waterlevels were determined by Karl Fisher analysis using a Metrohm 756 KFCoulometer and HYDRANAL Coulomat AG reagent. Melting points weredetermined using a Mettler Toledo FP62 melting point apparatus. pH wasmeasured using a calibrated Orion Model 290A pH meter. Proton and ¹³CNMR spectra were recorded on a Bruker Avance 300 MHz spectrometer.

Chiral HPLC analysis was carried out at λ=240 nm by injecting 10 μL ofsample dissolved in mobile phase onto a (R,R)WHELK-O 1.5 μm 250×4.6 mmcolumn (Regis Technologies) and eluting with a 1.0 mL/min flow of95/5/0.4 (v/v/v) hexanes/2-propanol/acetic acid. For solid samples ofthe CPTA/CAF D-Base diastereomeric salt, the solid was added to aqueoushydrochloric acid and the CPTA was extracted into methylene chloride;after removing the solvent from the methylene chloride layer, theresidue was dissolved in mobile phase for analysis.

Achiral HPLC analysis was carried out at λ=220 nm by injecting 5 μL ofsample dissolved in mobile phase onto a Phenomenex LUNA 5 μm C18(2)250×4.6 mm column at 25° C. A 1.5 mL/min flow of the gradient startingat 66 vol % water/34 vol % acetonitrile/0.1 vol % trifluoroacetic acidand increasing linearly to 26 vol % water/74 vol % acetonitrile/0.1 vol% trifluoroacetic acid at 20 minutes was used.

For analysis of acidic solutions of esters, such as halofenate,acetonitrile was used as the injection solvent. When determined, productconcentrations for CPTA and halofenate were evaluated by HPLC assayusing the external standard method and the achiral analysis procedure atsample concentrations of less than 2.5 mg/mL.

Example 1

Previous resolution of CPTA has been reported in U.S. Pat. No.3,517,050, in which cinchonidine was used as the chiral base, and the(+)-enantiomer of CPTA precipitated as the diastereomeric salt. Onemajor drawback to this procedure was that the desired (−)-enantiomerremained in the mother liquor, making separation of a pure(−)-enantiomer fraction difficult.

This example shows the results of resolving a racemic mixture of CPTAusing a variety of different chiral bases to obtain a solidenantiomerically enriched (−)-isomer. Unlike the previous method,methods of the present invention allow the solid enantiomericallyenriched (−)-CPTA to be readily isolated from the solution.

Racemic CPTA was prepared by the potassium hydroxide hydrolysis ofracemic halofenate. For chiral base screening, equal molar mixtures ofCPTA and the chiral base were mixed in ethanol, methanol and acetone inglass vials, and the solutions were allowed to stand undisturbed. Afterholding overnight at ambient temperature, the samples that remained insolution were placed in a refrigerator at 5° C. After holding overnightin the refrigerator, a small amount of water was added to the samplesthat remained a solution in ethanol. After four days at ambienttemperature, the aqueous ethanol solutions were placed back in therefrigerator. All of the samples remained in the refrigerator, and wereperiodically checked for precipitate formation over the course of amonth. A list of the bases and solvent conditions examined, andtemperatures at which crystalline salts were found is shown in Table 1.TABLE 1 Bases Examined for CPTA Resolution. Solvent System Base EtOHEtOH (aq) Acetone MeOH S-(-)-Methylbenzylamine E E E E Quinine C (22 °C.) C (22° C.) C (22 ° C.) Quinidine E E L-Tyrosine Hydrazide C (22 °C.) L-Leucine Methyl Ester Hydrochloride* E E 1-2-Amino-1-butanol E E EE Brucine E E E E (S)-(+)-2-Pyrrolidine-methanol E E E E(S)-(+)-2-Amino-3-methyl-1-butanol E (S)-(+)-2-Amino-1-propanol E(S)-(-)-2-Amino-3-phenyl-1-propanol E (1S,25)-(+)-Pseudoephedrine E E EE (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E(1S,2S)-(+)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol C (5 ° C.)(1R,2S)-(-)-Norephedrine E E E E (1R,2S)-(-)-Ephedrine E(1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol C (22 ° C.)(+)-Cinchonone E E E E (-)-Cinchonidine C (22 ° C.) (-)-Strychnine E E EEE - EvaluatedC - Crystallized at (Temperature)*-With 1 mol/mol of Aqueous Sodium Hydroxide

Four chiral bases, quinine, L-tyrosine hydrazide, (−)-cinchonidine, andboth enantiomers of 2-amino-1-(4-nitrophenyl)-1,3-propandiol, were foundto give crystalline salts from racemic CPTA. For samples thatcrystallized, the solid was isolated by filtration, and both the solidphase and mother liquor were analyzed by chiral HPLC to determine theenantiomeric composition of both streams. The results from the screenare shown in Table 2. Three of the bases shown in Table 2 gave the(+)-enantiomer enrichment in the solid phase. TABLE 2 Results fromChiral Base Screen. Mother Solid Liquor % Yield Base Solvent Temp ° C. %(+) % (−) % (+) % (−) Calculated L-Tyrosine Hydrazide Acetone 22 86.613.4 40.7 59.3 20.3 (-)-Cinchonidine Ethanol 22 66.8 33.2 12.0 88.0 69.3(1S,2S)-(+)-2-Amino-1-(4- Ethanol 22 93.2  6.8 28.5 71.5 33.2nitrophenyl)-1,3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9 50.1Acetone  22 28.2 71.8 58.9 41.1 28.9 Acetone*  5 23.0 77.0 83.5 16.555.4 Methanol 22 25.8 74.2 53.0 47.0 10.9 2-Propanol  30 43.2 56.8 64.335.7 67.6 2-Propanol** 30 40.4 59.6 78.8 21.1 75.0 2-Propanol*  21 42.357.7 59.1 40.9 53.9*More Dilute**Slower Cooling Profile

Included in Table 2 is the percent yield of solid calculated from theisomeric ratio in the solid and mother liquor streams. The equation usedis shown below. The maximum theoretical yield with 100% isomeric purityis 50%. Yields over 50% indicate inclusion of the other isomer.

Equation to calculate yield from isomer ratios.

Set: a=area % Component 1 in starting material; b=area % Component 2 instarting material; x=area % Component 1 in isolated; y=area % Component2 in isolated; w=area % Component 1 in mother liquor; z=area % Component2 in mother liquor; E=g material isolated; F=g material in motherliquor.

And: a+b=100%; E+F=1

Then: xE+wF=a; yE+zF=b

Solving: xE+w(1−E)=a; yE+Z(1−E)=b

E=isolated yield=(a−w)/(x−w)=(b−z)/(y−z)

Example 2

This example shows the results of resolving CPTA with CAF D base inethanol and 2-propanol.

The results for ethanol and 2-propanol are summarized in Table 3 below.For this evaluation, the slurries were sampled at various points in thecooling profile, and the enantiomeric composition of both the solid andsolution phases determined. From this information, the % ee of the solidphase and expected weight percent yield (maximum 50% yield with 100%ee), calculated from the isomer ratio, were determined. Included inTable 3 is the yield of (−)-CPTA, which is derived from the weightpercent yield and the (−)-CPTA content of the solid phase (maximum 100%yield with 100% ee).

In this particular study, the best results in ethanol used 1 mole of CAFD Base per mole of CPTA. Approximately 72% yield of the (−)-CPTA CAF DBase salt was calculated from the chiral composition of both phases,with an 87.6% ee of the (−)-CPTA salt in the solid phase. Use of onemolar equivalent of CAF D Base in 2-propanol at a similar concentrationgave a lower resolution. Higher enantiomeric enrichment was achievedwhen 0.55 mole of CAF D Base per mole of CPTA was used. Under theseconditions, approximately 76-79% yield of the (−)-CPTA CAF D Base saltwas calculated from the phase compositions, with an 87-90% ee of(−)-CPTA in the solid phase. Calculated weight percent yields, which donot take into account physical losses, were 41 to 42%; actual weighedisolated yields were 37 to 39%. TABLE 3 Resolution of CPTA with CAF DBase. wt % mole/mole Solid M.L. % Yield % Yield CPTA base T ° C. % (+) %(−) % (+) % (−) % ee 50% Max (-)-CPTA Ethanol 13.68 1.02 11 10.2 89.875.8 24.2 79.7 39.4 68.9  0 8.9 91.1 76.4 23.6 82.3 39.1 69.9 −9 6.293.8 78.0 22.0 87.6 39.0 72.4 14.09 0.50 18 6.6 93.4 55.5 44.5 86.7 11.220.7 −5 10.3 89.7 59.7 40.3 79.3 19.7 35.0 2-Propanol 15.72 1.01 12 45.954.1 66.9 33.1 8.2 80.4 85.8 −8 46.6 53.4 68.0 32.0 6.7 84.2 87.1 16.60.50 36 8.3 91.7 69.6 30.4 83.5 32.0 58.6 22 10.2 89.8 73.9 26.1 79.637.5 62.3  2 8.0 92.0 74.9 25.1 84.0 37.2 68.5 16.7 0.55 49 26.3 73.764.5 35.5 47.4 38.0 56.1 50 7.5 92.5 63.3 36.7 85.0 23.8 44.0 20 6.793.3 79.7 20.3 86.6 40.7 75.6 16.7 0.55 50 8.8 91.2 64.2 35.8 82.3 25.646.6 35 9.1 90.9 69.0 31.0 81.7 31.7 57.6  6 5.2 94.8 75.0 25.0 89.635.8 67.9  5 5.7 94.3 81.9 18.1 88.6 41.8 78.9  1 5.3 94.7 82.2 17.889.5 41.9 78.8 18.34 0.54  6 6.3 93.7 82.1 17.9 87.3 42.4 79.2

Recrystallization of the CPTA CAF D Base salt from 2-propanol increasedthe optical purity from approximately 87% ee to 98% ee with 87% massrecovery, or 93% recovery based on the (−)-CPTA content of the feed(Table 4). TABLE 4 Recrystallization of (-)-CPTA CAF D Base from2-Propanol. % ee M.L. wt % % Yield % ee Feed wt % Salt Isolated % (+) %(−) Yield (-)-CPTA 86.6 13.0 97.7 48.8 51.2 87.8 93.3 87.3 12.9 98.045.0 55.0 87.8 92.8

Overall, an approximately 35% yield out of a maximum 50% of the (−)-CPTACAF D Base salt, with an optical purity of approximately 98% ee, wasobtained from racemic CPTA.

Crystallization of optically enriched enantiomers often increases thechiral purity. Following removal of the resolving agent, crystallizationof (−)-CPTA from methylcyclohexanone will also increase the opticalpurity to some degree. In one experiment, crystallization of (+)-CPTAincreased the optical purity from 99.1 to 100% ee; the mother liquor was95% ee.

Example 3

This example illustrates the solubility profiles of CAF D Base salt of(+)- and (−)-isomers of CPTA in 2-propanol.

To aid in optimization of the CPTA resolution using CAF D Base, thesolubility profiles of both of the diastereomeric salts in 2-propanolwere determined. The results are shown in FIG. 1. The (+)-CPTA CAF DBase salt was prepared using cinchonidine-resolved (+)-CPTA. As FIG. 1shows, the desired (−)-CPTA diastereomer is approximately three timesless soluble than the (+)-CPTA form. Equations describing thesolubilities included in the figure were calculated by least squaresanalysis (R²>0.99). The data point for the (−)-CPTA salt at 82° C. wasnot included in determining the equation, but closely fits thecalculated solubility.

Racemization of the undesired CPTA enantiomer could be recycled backinto the process. Thus, it was found that heating an enantiomericallyenriched undesired isomer of CPTA in 1 N aqueous sodium hydroxide atreflux resulted in racemization in less than one hour. No otherby-products were detected by HPLC analysis of the isolated CPTA.

Example 4

This example illustrates a method for obtaining (+)-CPTA.

A 2-L round-bottom flask with an overhead stirrer was charged with 33.0g of crude (+)-CPTA—chinconidine salt, 610 mL of ethanol, and 125 mL ofmethanol. The slurry was heated to reflux to give a solution, thencooled. A very thick slurry formed at 42° C. The slurry was heated to68° C. to give a light slurry, then allowed to cool to ambienttemperature. The mixture was filtered at 26° C. and rinsed with 150 mLof ethanol to give, after drying under vacuum at 40° C., 23.48 g of(+)-CPTA—chinconidine salt. The recrystallization procedure was repeatedwith 600 mL of ethanol and 120 mL methanol to give 18.23 g of(+)-CPTA—chinconidine salt (55% recovery from two crystallizations). No(−)-CPTA was detected by chiral chromatography, although the degree ofseparation did not allow for an assessment of low levels (the halofenatechiral analysis conditions were also used at that time for the CPTAanalysis).

A 3.61 g sample of the purified salt was mixed with 50 mL of water and50 mL of toluene, and 2.9 g of sulfuric acid was added. The organicphase washed with 30 mL of water, then evaporated to a residue. Theresidue was crystallized from 20 mL of cyclohexane to give 1.22 g of(+)-CPTA. Alternatively, 6.3 g of the (+)-CPTA—chinconidine salt (10.2mmol) was mixed with 56 g of diethyl ether and 29 g of water, andacidified to a pH of 1.9 with drops of sulfuric acid. The organic phasewashed with 25 mL of water, dried (magnesium sulfate), filtered, andevaporated to a residue. The residue was stirred with 22 mL ofmethylcyclohexane at ambient temperature to form a slurry. The slurrywas warmed to 40° C., then cooled in an ice bath and the solid isolatedby filtration to give, after drying at 40° C. under vacuum, 2.62 g (7.92mmol, 78% yield) of (+)-CPTA.

Example 5

This example illustrates a method for synthesizing (+)-halofenate from(+)-CPTA.

A 25-mL round-bottom flask was charged with 0.91 g of (+)-CPTA and 2.6 gof thionyl chloride, and the mixture heated to reflux to give asolution. Conversion to acid chloride was monitored by quenching asample with methanol and analyzing the product with HPLC. To the acidchloride solution was added 4.8 g of diethyl ether, and this solutionwas added to 2.0 g of N-acetylethanolamine in 12 mL ofN,N-dimethylformamide (DMF) with 0.37 g of pyridine chilled in an icebath. The resulting solution was added to 25 mL of water and 30 mL ofdiethyl ether. The organic phase was separated, washed with 25 ml ofwater, dried (MgSO₄), and filtered to give, after removal of thesolvent, 0.92 g of an oil. HPLC analysis showed 45 area % of halofenateand 50 area % of CPTA. Chiral HPLC analysis indicated that thehalofenate was 99.78% ee of the (+)-enantiomer.

Example 6

This example illustrates a method for preparing racemic CPTA.

A 2-L round-bottom flask with an overhead stirrer was charged with 102.7g of halofenate, 500 mL of water, and 16.3 g of 2-propanol. The slurrywas stirred, and 32.3 g of aqueous 45% potassium hydroxide was added.After heating to reflux for 1 hour, the solution was cooled to ambienttemperature and charged with 380 mL of hexanes. The pH was adjusted from12.5 to 2 with 24.57 g of 37% hydrochloric acid. The three phase mixturewas heated to 60° C. to give two phases. The lower aqueous phase wasremoved and extracted with 50 mL of hexanes. The combined organic layerswere heated to distill at atmospheric pressure to remove 100 mL ofcloudy distillate. The solution was cooled to 30° C. and seeded withCPTA. A slurry formed. The slurry was cooled in an ice bath and thesolid isolated by filtration to afford 64.0 g (78.4% yield) of racemicCPTA, i.e., (4-chlorophenyl)(3-trifluoro-methylphenoxy)acetic acid.

Example 7

This example shows representative results of chiral resolution screeningin ethanol using a variety of chiral bases.

A sample of 1.16 g (3.51 mmol) of CPTA was dissolved in 6.98 g ofethanol to give a solution (0.431 mmol/g). Glass vials were individuallycharged with the amounts of each base listed in Table 5, and the amountof the ethanolic CPTA solution calculated to give a 1 to 1 molar ratioof acid to base was added. In some cases, a small amount of ethanol wasadded to wet the base prior to addition of the CPTA solution. The vialswere allowed to stand overnight at ambient temperature. Vials 7G and 71gave precipitates. A sample of each supernate was removed and analyzedby chiral HPLC analysis. The solids were isolated by filtration, andalso analyzed. Some of the results are shown in Table 2 (see Example 1above). The remaining vials were placed in a refrigerator at 5° C. Afterone day, 7E give a precipitate. The sample was analyzed as previouslydescribed. The remaining vials were charged with 50 μL of water, andheld at ambient temperature for three days before placing in therefrigerator. No additional precipitates were noted after one month.TABLE 5 Base Screening in Ethanol. wt CPTA Wt Solution Base EtOH WaterBase (g) (g) Added Added 7A S-(-)-Methylbenzylamine 0.8836 0.4620 0 g   0.05 g 7B 1-2-Amino-1-butanol 0.8198 0.0314 0    0.05 7C(1R,2S)-(-)-Norephedrine 0.5273 0.0342 0.2007 0.05 7D(1S,2S)-(+)-Pseudoephedrine 0.7295 0.0515 0.1459 0.05 7E(1S,2S)-(+)-2-Amino-1-(4- 0.5580 0.0510 0.1228 0  nitrophenyl)-1,3-propanediol 7F (1,2S)-(+)-2-Amino-1-phenyl- 0.56400.0405 0.1287 0.05 1,3-propanediol 7G (-)-Cinchonidine 0.3484 0.43900.3637 0   7H (+)-Cinchonine 0.6409 0.0796 0.2103 0.05 7I Quinine 0.53910.0750 0.1735 0   7J (-)-Strychnine 0.5812 0.0828 0.2295 0.05 7K Brucine0.7566 0.1287 0    0.05 7L (S)-(+)-2-pyrrolidine- 0.8681 0.0383 0   0.05 methanol

Example 8

This example shows representative results of chiral resolution screeningin acetone using a variety of chiral bases.

A sample of 1.67 g of CPTA was dissolved in 7.57 g of HPLC grade acetoneto give a solution. Glass vials were individually charged with theamounts of each base listed in Table 6, and the amount of the CPTAsolution calculated to give a 1 to 1 molar ratio of acid to base wasadded. In some cases, a small amount of acetone was added and themixture was warmed to about 40° C. to give a solution. Additionally,0.300 mL of 1 N sodium hydroxide was added to vial 16M. The vials wereallowed to stand overnight at ambient temperature. Vial 16D formed aprecipitate, and was analyzed as described above. Some of the resultsare summarized in Table 2 (see Example 1). The remaining vials wereplaced in the refrigerator. Vial 16 N formed a precipitate, and wasanalyzed. Vial 16G formed a very light precipitate. After one week, vial16L was found to contain a precipitate. The sample was analyzed aspreviously indicated. No additional precipitates were noted. TABLE 6Base Screening in Acetone. wt CPTA Wt Acetone Base Solution (g) Base (g)Added (g) 16A (1R,2S)-(-)-Norephedrine 0.8568 0.0704 16B(1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol 0.1824 0.0168 16CS-(-)-Methylbenzylamine 0.8948 0.0592 16D Quinine 0.1968 0.0347 0.85 16E(S)-(+)-2-pyrrolidine-methanol 0.8181 0.0452 16F Brucine 0.2163 0.046316G (+)-Cinchonine 0.3987 0.0630 16H (1S,2S)-(+)-Pseudoephedrine 1.08350.0974 16I (-)-Strychnine 0.1462 0.0265 0.25 16J Quinidine 0.3753 0.066316K 1-2-Amino-1-butanol 0.7248 0.0353 16L L-Tyrosine Hydrazide 0.45080.0472 0.39 16M L-Leucine Methyl Ester Hydrochloride 0.5585 0.0544 16NQuinine 0.4712 0.0829 2.00 16O (+)-Cinchonine 0.3363 0.0539 0.30

Example 9

This example shows representative results of chiral resolution screeningin methanol using a variety of chiral bases.

A sample of 2.00 g of CPTA was dissolved in 8.03 g of HPLC grademethanol to give a solution. Glass vials were individually charged withthe amounts of each base listed in Table 7, and the amount of the CPTAsolution calculated to give a 1 to 1 molar ratio of acid to base wasadded. Additionally, 0.300 mL of 1 N sodium hydroxide was added to vial27J. The vials were allowed to stand overnight at ambient temperature.Vial 27B solidified, and an additional 300 μL of methanol was addedbefore the sample was analyzed as described above. The remaining vialswere placed in the refrigerator. No additional precipitates were notedafter one month. TABLE 7 Base Screening in Methanol. wt CPTA wt solutionBase (g) base (g) 27A (1R,2S)-(-)-Ephedrine  0.4896 g  0.0478 g 27BQuinine 0.1420 0.0282 27C (+)-Cinchonine 0.1822 0.0324 27D1-2-Amino-1-butanol 1.0012 0.0539 27E S-(-)-Methylbenzylamine 0.78920.0576 27F (1S,2S)-(+)-Pseudoephedrine 0.7600 0.0749 27G Brucine 0.18910.0436 27H Quinidine 0.5845 0.1144 27I (1S,2S)-(+)-2-Amino-1-phenyl-1,3-0.3032 0.0299 propandiol 27J L-Leucine Methyl Ester Hydrochloride 0.50330.0545 27K (S)-(+)-2-Pyrrolidine-methanol 0.7133 0.0434 27L(1R,2S)-(-)-Norephedrine 1.1788 0.1070 27M (-)-Strychnine 0.4525 0.090527N (S)-(+)-2-Amino-3-methyl-1-butanol 0.1478 0.0092 27O(S)-(+)-2-Amino-1-propanol 0.9268 0.0417 27P(S)-(-)-2-mino-3-phenyl-1-propanol 0.3406 0.0307

Example 10

This example shows the result of resolving CPTA with quinine.

A 150-mL jacketed bottom-drain flask was charged with 2.70 g (8.17 mmol)of CPTA, 2.65 g (8.17 mmol) of quinine, and 50 mL of 2-propanol. Themixture was heated to 70° C. to give a solution, then cooled to 30° C.at a rate of 0.2° C./min and held for 2 hours to give a slurry. ChiralHPLC analysis of a sample showed 42.88 and 56.47 area % of (+) and(−)-CPTA, respectively, in the solid phase, and 61.54 and 34.19 area %of (+) and (−)-CPTA, respectively, in the solution. The slurry washeated to 60° C., then cooled to 30° C. at a rate of 0.04° C./min andheld overnight to give a slurry. Chiral HPLC analysis showed 29.94 and44.19 area % of (+) and (−)-CPTA, respectively, in the solid phase, and77.54 and 20.88 area % of (+) and (−)-CPTA, respectively, in thesolution. The slurry was diluted with 50 mL of 2-propanol and heated to57° C. to give a solution, then cooled to 30° C. at a rate of 0.2°C./min. A slurry started to form after 1 hour at 30° C. The mixture wasstirred for 2 days at ambient temperature, then the solid was isolatedby filtration and rinsed with 2-propanol to give, after drying undervacuum, 2.89 g (54% yield by mass) of the quinine salt of CPTA. ChiralHPLC analysis found 42.25 and 57.75 area % of (+) and (−)-CPTA,respectively, in the solid phase and 56.56 and 39.20 area % of (+) and(−)-CPTA, respectively, in the mother liquor. The results are alsoincluded in Table 2 (see Example 1).

Example 11

This example shows the result of resolving CPTA with CAF D base.

A 150-mL bottom-drain flask was charged with 19.54 g of CPTA, 6.82 g ofCAF D Base (i.e., D-threo-(−)-2-amino-1-(nitrophenyl)-1,3-propandiol),and 80.2 g of 2-propanol. The mixture was warmed to 70° C. to give asolution, then cooled to a jacket temperature of 5° C. at a rate of 0.1°C./min. The mixture was hazy at 62° C. After holding at 6° C. for 9hours, the solid was isolated by filtration, rinsed with 5 mL of2-propanol, and dried at 40° C. under vacuum to give 12.03 g (37.4 wt %yield) of (−)-CPTA CAF D Base salt. Chiral HPLC analysis of the solidfound 6.34 area % of (+)-CPTA and 93.46 area % of (−)-CPTA; the motherliquor contained 81.41 area % of (+)-CPTA and 17.76 area % of (−)-CPTA.

Example 12

This example shows the result of recrystallizing (−)-CPTA CAF D Basesalt.

A 150-mL bottom-drain flask was charged with 8.00 g of the (−)-CPTA CAFD Base salt (from Example 11 above) and 54.2 g of 2-propanol. Themixture was heated to reflux to give a solution, then cool to a jackettemperature of 20° C. at a rate of 0.1° C./min and held at an internaltemperature of 22° C. for 6 hours. The solid was isolated by filtration,rinsed with 2-propanol, and dried at 40° C. under vacuum to give 6.93 g(86.6 wt % recovery) of (−)-CPTA CAF D Base salt (m.p. 184-185° C.). Thesolid contained 0.995 area % of (+)-CPTA and 99.01 area % of (−)-CPTA;the mother liquor contained 44.53 area % of (+)-CPTA and 54.47 area % of(−)-CPTA. The reactor was cleaned out with acetone. The acetone wasevaporated to a residue of 0.27 g (3.4 wt %).

Example 13

This example illustrates a method for preparing (+)-CPTA CAF D Basesalt.

A 1-L flask was charged with 10.94 g (17.5 mmol) of the (+)-CPTAcinchonidine salt, 200 mL of water, and 100 mL of methylene chloride.The pH was adjusted to 1.9 by the addition of 1.8 g of sulfuric acid.The organic layer washed three times with 100-mL portions of diluteaqueous sulfuric acid, dried (magnesium sulfate), filtered, andevaporated to a residue of 5.79 g. The residue was dissolved in 22.2 gof 2-propanol, and 3.5 g of CAF D Base was added. The resulting slurrywas heated to reflux to give a solution, then cooled to ambienttemperature and the slurry stirred for three hours. After cooling in anice bath, the solid was isolated by vacuum filtration, rinsed with 5 mLof 2-propanol, and dried under vacuum at 40° C. to give 7.39 g (80%yield) of (+)-CPTA CAF D Base salt (m.p. 172-173° C.).

Example 14

This example shows solubility of diastereomeric CPTA-CAF D base salts in2-propanol.

Samples of (−)-CPTA CAF D Base and (+)-CPTA CAF D Base (>98% ee) wereadded to 2-propanol in the amounts shown in Table 8, and mixed using anultrasonic bath. All samples remained slurries. The slurries were heldovernight at the temperature listed, then samples of the supernates wereremoved and analyzed by quantitative HPLC analysis to determine the CPTAconcentration. The results are shown in the table, and in FIG. 1.Additionally, 8.00 g of (−)-CPTA CAF D Base salt required 54.2 g of2-propanol for solution at 82° C. (14.7 wt %). This data point wasincluded in FIG. 1, but not included in the solubility equation. TABLE 8Solubility in 2-Propanol. Wt Salt (g) Wt 2-propanol (g) T ° C. Wt % insolution (-)-CPTA CAF D Base Salt 0.31 1.17 45.3 2.35 0.23 2.48  7.80.376 0.21 1.31 19.4 0.688 (+)-CPTA CAF D Base Salt 0.25 1.84 20.0 1.850.27 1.83 45.8 6.03 0.17 2.09  8.5 1.32

Example 15

This example illustrates a method for racemizing enantiomericallyenriched CPTA.

A 50-mL round bottom flask was charged with 0.31 g of (−)-CPTA (68.7%ee) and 9.4 g of 1N sodium hydroxide. The solution was heated to refluxfor one hour, then cool to ambient temperature and acidified with 1 g of37% hydrochloric acid. The CPTA was extracted into methylene chloride,and the solvent was evaporated to an oil of 0.46 g. HPLC analysis found99.4 area % of CPTA, and chiral HPLC analysis found a 50/50 mixture ofthe CPTA enantiomers.

Example 16

This example illustrates a process for resolving a racemic mixture ofCPTA using CAF D-Base under a variety of crystallization conditions.

The general crystallization procedure was to charge CPTA, CAF D-Base,and 2-propanol at room temperature and heat to a solution at about 75°C. The solution was cooled to about 60° C. and held until nucleationoccurred. Several batches were seeded with (−)-Salt (i.e., salt of(−)-CPTA and CAF D-Base) to induce nucleation. After the slurry haddeveloped over about an hour, the vessel was cooled to the isolationtemperature. The first 5 entries in FIG. 2 used a slow cooling rate ofabout 0.05-0.10° C./minute to reach the isolation temperature. The otherexperiments used a faster cooling rate of 0.25-0.40° C./minute. A fiberoptic probe is inserted directly into the crystallizer to determine theslurry density.

The amount of CAF D-Base added and the solute concentration are some ofthe important variables which give rise to the final batch composition.The tendency for the (+)-Salt (i.e., salt of (+)-CPTA and CAF D-Base) toremain supersaturated for varying amounts of time is believed to be amajor cause for variability in some experiments. This is demonstrated inentry 5 in FIG. 2, whereby the slurry was held for 8 hours at 13° C. andproduced high purity crystal (99.7% (−)-Salt). Three hours later, anincrease in the signal of the fiber optic probe indicated the likelynucleation of the (+)-Salt. After another 27 hours, the slurry wasisolated and the crystal product contained a (−/+)-CPTA ratio of83.3/16.7%. Analysis of the crystal product by HPLC gives the ratio of(−)-CPTA and (+)-CPTA. Since the free CPTA in solution is undersaturatedthe crystal analysis therefore gives the diasteriomeric salt ratio.Mother liquors contain both dissolved salt and free CPTA. Analysis byHPLC reports the combined amount of each enantiomer as CPTA. Similarly,entry 6 of FIG. 2 shows that the slurry was held for 20 hours at 1° C.and produced high purity salt (>98% (−)-CPTA). After heating to 17° C.,the (+)-Salt nucleated and gave poorer quality product[(−/+)-CPTA=81.2/18.8%].

In other trials, nucleation of the (+)-Salt occurred more quickly, as inentries 2, 8, and 10 of FIG. 2. A crystallization is desirable for whichisolation could be done near, preferably just above, the saturationtemperature of the (+)-Salt.

At a loading of 3.9 g of 2-propanol per gram of CPTA and with 0.45equivalent of CAF D-Base, an isolation at room temperature appears to bevery near the saturation level (or within the metastable zone) of the(+)-Salt. Entry 12 in FIG. 2 started with 0.43 equivalents of base, andthe crystal product at 21° C. remained pure (>99% (−)-Salt), even afterseeding with (+)-Salt. After adding more CAF D-Base to give 0.45equivalents, the slurry was held for 14 hours, and then for 6 more hoursafter seeding with (+)-Salt. The crystal product analyzed at 98.7%(−)-CPTA ratio. Increasing the total base to 0.47 equivalent gavecrystal product which slowly increased in (+)-Salt composition to(−/+)-CPTA=92.3/7.7%.

Entry 11 of FIG. 2 (3.9 g of 2-propanol per gram of CPTA, 0.45 eq. base)maintained high purity of the (−)-Salt (99.1%) after 14 hours, but uponaddition of more base to 0.48 eq., the resulting ratio of the productwas (−/+)-Salt=89.2/10.8%. Entry 9 of FIG. 2 (at 0.45 eq. base)maintained 99.5% (−)-Salt purity after 16 hours at 22° C. Calculatedyields of (−)-CPTA from the three batches under these conditions were70.7-71.6%. Calculated yields are derived from a forced mass balancefrom the racemic CPTA feed, by knowing the crystal and mother liquorcomposition of (−)-CPTA and (+)-CPTA.

These loadings of about 0.45 equivalent of CAF D-Base and about 4 g of2-propanol per gram of CPTA provide a high purity (−)-Salt (>98.5%)product, which can be used without a further recrystallization.

Example 17

This example provides a model to describe the resolution/crystallizationof CPTA salt.

The concentration of free CPTA depends on the amount of base charged andthe solvent loading. For example, a resolution of CPTA by charging 4.0grams of 2-propanol and 0.50 equivalent of CAF D-Base, results information of the salt in 2-propanol which contains 11% free CPTA. Thissolvent possesses greater solubility for both the (−)-Salt and the(+)-Salt, and was determined as shown in FIG. 3. FIG. 3 also includesthe solubility data in pure 2-propanol, expressed in gram of componentper gram of 2-propanol. As FIG. 3 shows the curves for the respectivesalts are of similar shape.

By other combinations of the loading of CPTA, CAF D-Base, and2-propanol, a system resulting in 11.0% free CPTA in 2-propanol can alsobe attained, as shown in FIG. 4. As FIG. 4 shows, the loading forvarious experiments in FIG. 2 did not usually fall exactly on this line.However, the (−)-Salt and the (+)-Salt solubility can be estimated asfollows: a loading which gives a point above the “11.0% free CPTA” lineis more dilute (i.e., <11.0% free CPTA in 2-propanol), and exhibits alower solubility than the “11.0%” line. Conversely, points below the“11.0%” line result in solvent containing >11.0% free CPTA, and the saltsolubility is greater than determined in FIG. 3. To estimate componentsolubility, a constant multiplier factor, k, was used. The modifiedsolubility equations for the (−)-Salt and the (+)-Salt are thereforeS⁽⁻⁾=0.01421ke^(0.02613T) and S₍₊₎=0.02868ke^(0.02771T).

Even with a good estimation of the (−)-Salt and the (+)-Salt solubilityby adjusting k, one can still not describe the crystallization, for theother unknown is the ratio of (−)-Salt and (+)-Salt which is formed uponaddition of the resolving agent base. One of the more detailedexperiments is shown in FIG. 5 (see also FIG. 2). This experiment used0.75 equivalent of base and when sampled at 21.5° C., gave the productwith (−/+)-Salt ratio of 66.4/33.6%. By heating the slurry andcontinuing to take samples, the saturation line for both (−)-Salt andthe (+)-Salt in the solvent can be followed.

To match the solubility model to the actual data, a regression techniquewas used, whereby the solubility factor k and the feed ratio of (−)-Saltand (+)-Salt were manipulated to give an answer (i.e., crystalcomposition, mother liquor composition, and crystal yield) which wasconsistent with the observed data. By selecting k=0.68 and a feed ratiofor 0.75 equivalent of salt at 58.1% (−)-Salt/41.9% (+)-Salt (i.e.,0.436 eq. of (−)-Salt and 0.314 eq. of (+)-Salt were formed uponaddition of CAF D-Base), a good agreement was obtained. FIG. 6 shows thecomparison. The solubility model allows calculation of the complete massbalance for the isolation: the amount of (−)-Salt and (+)-Salt in thecrystal, the amount of (−)-Salt and (+)-Salt in the mother liquor, andalso the amount of (−)-free CPTA and (+)-free CPTA in the mother liquor.One procedure for quantifying (−/+)-Salt and (−/+)-free CPTA in motherliquor by an extractive work-up, using solubility differences, isprovide in Example 19 below.

The regression technique with the solubility model was applied to otherexperiments which fed differing amounts of resolving agent. Using acombination of the solubility factor k and the composition of the saltas feed (i.e., the ratio of (−)-Salt and (+)-Salt which was formed uponthe addition of base), the model tended to a unique solution which fitthe experimental results. From these, the graph in FIG. 7 wasconstructed. This result shows that as more resolving agent is added(above the extrapolated minimum point of 0.34 eq.), an increasing amountof (+)-Salt is formed. Without being bound by any theory, in someembodiments, it is believed that if less than 0.34 equivalent is added,the CAF D-Base will coordinate substantially only with (−)-CPTA, formingalmost exclusively (−)-Salt. Additionally, by aid of the curve in FIG.7, the amount of (−)-CPTA and (+)-CPTA (free acid) can be calculated.Between 0.35-0.75 equivalent of base charged, the % ratio of{(−)-CPTA/total CPTA free acid} is around 25% (23.3-27.1%). The“selectivity” for the ratio of (−/+)-Salt that is formed thus isdependent on the amount of free (−)-CPTA that remains (in solution),which comes to an endpoint of about (−)-CPTA/(+)-CPTA=1/3. It isbelieved that once the (−)-CPTA concentration is depleted by addition ofabout 0.34 eq. of base to a (−/+)-CPTA ratio of 1/3, continued additionof base forms the (−/+)-Salt at a ratio of 1/3 (to keep free (−/+)-CPTAat a constant 1/3 ratio in solution).

Example 18

This example illustrates resolution of a racemic mixture of CPTA.

A 200-mL vessel was charged with 17.0 g of CPTA (51.4 mmol), 4.91 g ofCAF D-Base (23.1 mmol, 0.450 eq.), and 85 mL of 2-propanol. The mixturewas heated to a solution at 78° C., and then cooled at 0.5° C./min to54° C. About 12 hour later, the solution was seeded with (−)-Salt toinduce nucleation. After holding at 54° C. for about 1½ hours, theslurry was cooled to 22° C. at 0.25° C./minute. After holding for 14hours at 22° C., a small sample (˜5 mL) was taken and separated on a15-mL, medium-fritted funnel. The mother liquor was weighted and saved,and the solid washed with 2 mL of 2-propanol. The wash was weighed andsaved, and suction was continued to dry the crystal. Analysis by thestandardized HPLC system allowed calculation of weight % (−)-CPTA and(+)-CPTA in each stream. A mass balance around this sample (totalaccountability of CPTA in the crystal, mother liquor, and wash was 0.85g) gave a 31.9% isolated yield of crystal product from the total CPTA.Crystal purity was 99.1/0.9%=(−/+)-CPTA ratio by weight. FIG. 8 showsthe analytical and mass balance results in the rectangular boxes. Thecalculated yield (from CPTA) based on feed/mother liquor/crystalcomposition is given inside the circles. Abbreviations in FIG. 8 are asfollows: R.A.=resolving agent, x or xtal=crystal, ML=mother liquor,Yld=yield.

The vessel was seeded several times with crystal containing (+)-Salt,and about 2 hours later, 0.31 g of CAF D-Base (1.46 mmol, ˜0.03 eq.) wasadded. The vessel was sampled two times (see FIG. 8) before the finalisolation on a 60-mL medium-fritted funnel. The mother liquor was clear,pale yellow-gold, 59.1 g. The solid washed with 19.2 g of 2-propanol,with recovery of 18.8 g of wash solution. The washed solid (10.07 g) wasfurther dried by suction on the funnel for an hour to 8.36 g (15.4 mmolsalt). Analysis of all streams from the final isolation accounted for13.45 g (40.67 mmol) of CPTA. The final crystal product ratio was(−/+)-CPTA=89.2/10.8%, for an isolated yield of (−)-CPTA=33.8°/a (fromCPTA). The calculated yield of (−)-CPTA, based upon the feed, motherliquor, and crystal composition, was 35.0%.

Example 19

This example illustrates an extractive work-up process to quantify(−/+)-Salt and (−/+)-CPTA in Mother Liquor.

A mixture of the (−/+)-Salt, 80/20, was only sparingly soluble inmethylene chloride at about 0.016%, while racemic CPTA was considerablymore soluble at a little less than 3.4%. The final mother liquor fromseparation of entry 4 of FIG. 2 at 55.3° C. (see FIGS. 2 and 5) wasanalyzed by evaporating 0.1286 g to a glassy residue of 0.0242 g. Theresidue was dissolved in 5 mL of methylene chloride, seeded with(−/+)-Salt=80/20, and allowed to stand overnight. The bulk of thesupernatant liquid was removed, 3 mL of methylene chloride were added,and the bulk of the liquid was removed and combined with the firstextract. The methylene chloride extract was evaporated to give a glassysolid, 0.0074 g, and then analyzed by HPLC. The remaining thick slurrywas evaporated to 0.0162 g and analyzed by HPLC. Results from theextractive work-up procedure are generally similar to the compositionpredicted by the solubility model, as shown in FIG. 9.

Example 20

This example shows solubility of (−)- and (+)-CPTA-CAF D-Base salts inalcohols containing CPTA.

“Solvent” was prepared by dissolving 2.40 g of racemic CPTA in 19.42 gof 2-propanol (Fisher HPLC Grade) or 4.90 g of racemic CPTA in 31.4 g ofethanol. The respective concentrations of CPTA in solution were 11.0%and 13.5%. Solubility of the (−)-CPTA•CAF D-Base Salt (i.e., (−)-Salt)or (+)-CPTA•CAF D-Base Salt (i.e., (+)-Salt) was determined by agravimetric method. At a given temperature, a portion of the supernatantliquid from a saturated solution was remove to a vial of known weight.The solution weight was determined, and the volatile solvent wasevaporated with a purge of nitrogen. The solid was further dried toconstant weight in a vacuum oven at about 50° C./1 mm Hg. The vial wasre-weighed to determine the loss of volatile solvent and weight of solidremaining. From this, the amount of dissolved CPTA from the “solvent”could be calculated. Subtracting the weight of total solid from the CPTAgave the weight of soluble salt in the solvent. Data are shown in FIGS.10A and 10B.

Example 21

This example illustrates a method for preparing enantiomericallyenriched (−)-halofenate.

CPTA was prepared in five steps, as discussed above, withoutintermediate isolation in about 85% yield following crystallization fromheptane. Resolution gave an average of 32% yield (max 50%) of >98%optically pure (−)-CPTA diastereomeric salt. After removing theresolving agent, the (−)-CPTA was esterified to give (−)-halofenate inabout 55% yield using thionyl chloride and N-acetylethanolamine. Byhydrolyzing the mother liquor residue with aqueous sodium hydroxide,(−)-CPTA can be recovered from the final product mother liquor andcycled back through the process. The resolving agent was isolated fromwater in about 90% recovery by a pH adjustment. Recovery andracemization of the (+)-CPTA using aqueous sodium hydroxide gave about90% recovery. Overall, the first pass yield from 4-chlorophenylacticacid was 15-17%. The entire eight-step process used three organicsolvents, and three solid isolation steps.

Example 22

This example illustrates a method for preparing CPTA.

The synthetic route to CPTA is outlined above. Following bromination ofthe acid chloride 1 in 1,2-dichloroethane to give 2,2-propanol was addedto give the isopropyl ester 3. The displacement reaction withα,α,α-trifluoro-m-cresol was accomplished using potassium hydroxide in2-propanol. Following a water quench and wash and removal of the1,2-dichloroethane, the liquid 3 was added to a solution ofα,α,α-trifluoro-m-cresol and potassium hydroxide in 2-propanol to give4. The 2-propanol solvent was removed, and the hydrolysis to CPTA wascompleted by heating with aqueous sodium hydroxide.

The sodium salt of CPTA can be isolated as a solid by simply cooling thereaction mixture. Better isolated yields were obtained, however, byisolation of the carboxylic acid. For isolation, the basic aqueous CPTAreaction mixture was acidified with hydrochloric acid, and the CPTA wasextracted into 1,2-dichloroethane. Solvent exchange of the separatedorganic phase from 1,2-dichloroethane to heptane afforded CPTA as awhite solid in approximately 85% yield from 4-chlorophenylactic acid.

Example 23

This example shows solubility of CPTA in 1,2-dichloroethane and heptane.

The solubility of racemic CPTA in 1,2-dichloroethane and heptane areshown in FIGS. 11 and 12, respectively. Included in the Figures are theequations for the least-squares fit of the data.

Based on the solubility profile of FIG. 11, a concentration ofapproximately 25 wt % CPTA in 1,2-dichloroethane at a temperature ofapproximately 35° C. was chosen for the CPTA extraction conditions.

CPTA crystallization from heptane was exothermic. Seeding of a solutionof approximately 170 g of CPTA in 500 mL of heptane at 46° C. resultedin a temperature increase to 54° C. as the crystallization progressed.Crystallization increased the CPTA purity as determined by HPLC analysisfrom 93-95 to >99 area %. HPLC assay of a crystallization mother liquor,which contained 15 area % of CPTA, found less than 3% yield loss to themother liquor. As the purity was improved by crystallization, isolatedyields were high, and the loss to the mother liquor was minor.

Example 24

This example shows yield of CPTA resolution under variety ofcrystallization conditions.

Results of CPTA resolution using CAF D-Base under variouscrystallization conditions are shown in FIG. 13. Final chiral purity foreach preparation, obtained after zero, one, or two recrystallizations,is in bold type. The molar ratio of the CAF D-Base was varied from 0.5to 0.56. The amount of 2-propanol solvent listed for thecrystallizations and recrystallizations are both based on the initialcharge of racemic CPTA. Chiral HPLC results for both the isolated solidsand mother liquors are normalized to 100%. The calculated yield andoverall yield are calculated from the ratio of the (+)-enantiomer and(−)-enantiomer forms in the isolated solids and mother liquors. Theactual percent yield in the last column is of weighed, dried material,and is based on a maximum yield of 50%.

Overall yields of the diastereomeric salt at >98% optical purity rangedfrom 28 to 35%, and averaged 32%. In one case, using the lowest ratio ofresolving agent, this was obtained without recrystallization (experiment2 in FIG. 13). The chiral purity of the first isolated solid ranged from73% to 98%. A single recrystallization was generally sufficient toobtain the desired optical purity. A high overall yield was obtainedwhen the mother liquor reached a 20/80 ratio of (−)-CPTA to (+)-CPTA.

FIG. 14 shows the cooling profiles for the resolution crystallizationslisted in order of decreasing yield of (−)-CPTA. Experiment number inFIG. 14 corresponds to the experiment number in FIG. 13. The isolatedyield of (−)-CPTA was determined using the calculated yield of FIG. 13and the percent of (−)-CPTA in the isolated material. In general, longerhold times at low temperatures led to an increase in yield.

Use of 0.45 molar equivalents of CAF D-Base consistently gave 35-37%yield of material that was >98% optically pure without the need forrecrystallization.

Example 25

This example shows a method for separating (−)-CPTA from the CAF D-Base.

To separate (−)-CPTA from the CAF D-Base, the diastereomeric salt wasmixed with 1,2-dichloroethane, and aqueous hydrochloric acid was addedto give a pH in the aqueous phase of less than about 2. The aqueousphase containing the hydrochloride salt of the CAF D-Base was separated.After a water wash of the organic phase, the bulk of the1,2-dichloroethane was removed by distillation to remove residual water.Complete solvent removal gave an oil.

Example 26

This example shows a method for esterifying (−)-CPTA without anysignificant racemization.

(−)-CPTA was reacted with thionyl chloride in 1,2-dichloroethane atreflux to yield a corresponding acid chloride. Reaction progress can bemonitored by HPLC analysis. A small amount of distillate was removed toremove excess thionyl chloride. The mixture was cooled, and a largeexcess of vacuum distilled N-acetylethanolamine was added. Stirring atambient temperature gave (−)-halofenate.

The esterification reaction mixture was quenched by adding the reactionmixture to an aqueous potassium carbonate solution. (−)-Halofenate wasisolated by solvent exchange and crystallization from the 6:1heptane:2-propanol. Results are summarized in FIG. 15.

First crop isolated yields ranged from 47 to 59% and averaged 55%. Thisisolated yield represents a reaction yield of 75 to 80% for this step. Asecond crop afforded a higher overall yield; however, the productquality was poorer with the second crop material.

Molar accountability of the CPTA loaded, found as isolated halofenate,and halofenate and CPTA in the mother liquor, ranged from 90 to 99%.

Example 27

This example shows a method for recovering and recycling (+)-CPTA.

Heating CPTA in aqueous base caused racemization. The remaining CPTAfrom the resolution step in Example 25 was approximately 47% ee of the(+)-enantiomer, which also contains residual CAF D-Base.

To recover and racemize the (+)-CPTA, the 2-propanol solvent was removedand replaced with 1,2-dichloroethane. Washing with water at a pH belowabout 2 removed the CAF-D-Base for subsequent recovery. Aqueous sodiumhydroxide was added, and the aqueous solution heated to reflux. The1,2-dichloroethane was either removed by distillation prior to theaddition of the basic solution, or by a phase separation followingaddition of the basic solution. An 89% yield of racemic CPTA wasisolated from heptane after heating an aqueous solution for four hourswith 1.4 molar equivalents of sodium hydroxide. Isolation of CPTA as acrystallized intermediate provided a more consistent quality feed forthe resolution step.

The solubility of the sodium salt of racemic CPTA in water, determinedand expressed as the acid form, is shown in FIG. 16. Addition of theisolated sodium salt to water gave a pH of about 9.5, and the solubilityprofile shown in the upper solubility curve. Addition of a small amountof sodium hydroxide to give a pH of about 12.6 decreased the aqueoussolubility to that shown on the lower curve.

Example 28

This example shows a method for producing CPTA from (+)-halofenate.

Addition of from 1 to 3 molar equivalents of sodium hydroxide to about10 wt % of 87% ee (+)-halofenate in water and warming to 50 to 60° C.resulted in a substantially complete hydrolysis to CPTA. Partialracemization to give approximately 70% ee (+)-CPTA occurred (Time=0 ofFIG. 17). The solution was heated to reflux, and the enantiomeric ratiomonitored over time. With 3 molar equivalents of base, almost completeracemization (<3% ee by the chiral HPLC analysis method) occurred inless than 2 hours at reflex. The pH dropped from 12.8 to 12.6 over thecourse of the racemization. A slightly longer reaction time was requiredwith 2 molar equivalents (pH 12.6 to 11.6). With 1 molar equivalent,racemization stopped at approximately 60 to 70% ee, with a final pH of9.4.

Use of 0.5 molar equivalents of sodium hydroxide left approximately 40%of the halofenate unhydrolyzed after 2 hours at 60° C.; heating toreflux overnight left approximately 1% halofenate at a final pH of 4.8.This did not significantly minimize racemization. The amount of CPTAproduced was 72.6% ee of the (+)-enantiomer.

Example 29

This example illustrates a method for recovering (−)-CPTA from(−)-halofenate crystallization mother liquor.

As noted previously and shown in FIG. 15, the (−)-halofenatecrystallization mother liquor contains a large amount of (−)-halofenateand (−)-CPTA. By hydrolysis of the (−)-halofenate, additional (−)-CPTAcan be generated as feed for the resolution step.

Hydrolysis of a (−)-halofenate crystallization mother liquor (88.3% eeof (−)-halofenate) at 50° C. and a final pH of 12.7 rapidly gave 65.8%ee (−)-CPTA. The (−)-CPTA was recovered as the CAF D-Base diastereomericsalt (96.4% ee) by addition of CAF D-Base to a 2-propanol solution. Fromthe amount of diastereomeric salt initially loaded, 55 mol % wasobtained as (−)-halofenate, 28% was recovered as the (−)-CPTA/CAF D-Basesalt, and 14 mol % remained as CPTA in the mother liquor.

Example 30

This example illustrates a method for recovering CAF D-Base.

The CAF D-Base is found in the acidic phase from separation of (−)-CPTAfrom the diastereomeric salt, and from the acidic wash step of the CPTArecovery from the resolution mother liquors. Basification with aqueoussodium hydroxide to a pH greater than about 12 resulted in precipitationwith good recovery in a form that was easily filtered. Results are shownin FIG. 18. Recovery from the diastereomeric salt was generally greaterthan 90%; recovery from the resolution mother liquor was lower.Concentrations in the aqueous solution ranged from about 5 to 20%.

The enantiomeric purity of the CAF D-Base can be determined by carefulanalysis of the melting point by DSC (D. Pitre, M. Nebuloni, and V.Ferri; Arch. Pharm. (Weinheim) 324, 525 (1991)). As the conglomerate ofthe (+)- and (−)-forms, e.g., racemate, melts more than 20° C. lowerthan the pure enantiomer, melting point was found to be a sensitivemethod for assessing enantiomeric purity. However, measurement of theenantiomeric purity of two of the samples by chromatographic separationof a derivative showed no loss of chiral purity. The enantiomeric purityof the recovered CAF D-Base, near the detection limit of the HPLCanalysis method, was indistinguishable from the source material.

Example 31

This example illustrates another method for preparing racemic CPTA.

A 500-mL round-bottom flask in a heating mantel and fitted with anoverhead stirrer and condenser was charged with 73.28 g (0.430 mol) of4-chlorophenylactic acid, 70 ml, of 1,2-dichloroethane, and 41 mL (0.56mol) of thionyl chloride. The mixture was warmed at 50 to 55° C. for 19h. The reaction mixture was analyzed by HPLC analysis. To the solutionof acid chloride was added 29 mL (0.57 mol) of bromine, and the solutionwas warmed at 70 to 75° C. for 20 h. The resulting α-bromo product wascooled in an ice bath and 100 mL (1.31 mol) of 2-propanol was addeddropwise. The maximum temperature reached was 17° C. After cooling to 4°C., the reaction mixture was added to water. The solution was warmed toambient temperature, and the aqueous layer was removed. The organicphase washed with 37 mL of water. The separated 1,2-dichloroethanesolution was evaporated to give 134.1 g of an oil.

A 1-L round-bottom flask with an overhead stirrer was charged with 34.0g (0.515 mol) of 85% potassium hydroxide and 370 mL of 2-propanol. Themixture was warmed to 41° C. using a water bath to dissolve much of thesolid. The mixture was cooled in an ice bath, and 73.8 g (0.455 mol) ofα,α,α-trifluoro-m-cresol was added dropwise. The maximum temperaturereached was 13° C. The solution was cooled to 5° C. before the dropwiseaddition of 134.1 g of the oil obtained above. The material was rinsedin with 18 g of 2-propanol. The slurry was evaporated to a residue, thencharged with 250 mL of water and 42.8 g (0.535 mol) of 50% aqueoussodium hydroxide. The mixture was heated to reflux for 1 h.

After cooling to ambient temperature, the mixture was diluted with 250mL of 1,2-dichloroethane, and the pH was decreased to 0.3 by thedropwise addition of 71 g (0.72 mol) of 37% hydrochloric acid. After aphase separation, the solvent was removed from the 1,2-dichloroethanephase to give 202.2 g of residue. The residue was treated with 131 g ofheptane, and evaporated to a residue of 164 g. The process was repeatedwith 97 g of heptane, giving 160 g of an oil. The residual oil wasstirred at ambient temperature with 257 g of heptane to give a slurry,which was chilled in an ice bath before isolation of the solid byfiltration. The filter cake washed with 49 g of heptane, then driedunder a vacuum to give 125.58 g (0.380 mol, 88% yield) of CPTA.

Example 32

This example illustrates a method for preparing a racemic mixture ofcompound 4 of Example 22.

A 50-mL round-bottom flask equipped with a magnetic stirrer and refluxcondenser was charged with 2.10 g (6.35 mmol) of racemic CPTA, 21 g of2-propanol, and 0.50 g (4.2 mmol) of thionyl chloride. HPLC analysisafter 90 minutes at reflux indicated 84.2 area % of 7 and 12.7 area % ofCPTA. An additional 1.0 g (8.4 mmol) of thionyl chloride was added togive less than 1 area % of CPTA. The solution was cooled to ambienttemperature and treated with 1.0 g (12 mmol) of solid sodiumbicarbonate. The solvent was evaporated, and the residue dissolved in 25mL of toluene. After washing with water (2×10 mL), the solvent wasevaporated to a residue of 2.31 g (6.2 mmol, 98% yield) of compound 4 ofExample 22 (95.8 area % of 7, 2.4 area % of toluene).

Example 33

This example illustrates a method for determining solubility of racemicCPTA.

A 100 mL water jacketed resin pot with a magnetic stirrer was connectedto a recirculating water bath and charged with 9.44 g of racemic CPTAand 16.78 g of 1,2-dichloroethane. The bath temperature was warmed to35° C., and the slurry was stirred for one hour. The agitator was shutoff, and the solid was allowed to settle for 30 min. A 0.1360 g sampleof the supernate was removed and diluted to 25.00 mL with acetonitrile,and the solution was assayed by HPLC analysis. Results for this and aseries of other measurements are shown in FIGS. 11 and 19. For analysisat about 2° C., a 0.54 g-sample of CPTA in 1.92 g of 1,2-dichloroethanewas stored in a refrigerator overnight before analysis of the supernateby HPLC analysis. The solubility of CPTA in heptane, included in FIG. 19shown in FIG. 12, was determined in a similar fashion.

Example 34

This example illustrates a method for resolving a racemic mixture ofCPTA.

A 1-L bottom-drain reactor was charged with 48.2 g (146 mmol) of CPTA,16.4 g (77.3 mmol) of(1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (CAF D-Base), and193 g of 2-propanol. The slurry was heated to 70° C. to give a solution,then cooled to 60° C. and held for 1 h. The resulting slurry was cooledat 0.25° C./min to a jacket temperature of 2° C. and held for 14 h; theinternal temperature was 4° C. The solid was isolated by vacuumfiltration and rinsed with 27 g of 2-propanol. The mother liquor andwash solution was sampled for HPLC analysis, and the results are shownin FIG. 13. The 50.48-g wetcake was reloaded to the 1-L reactor with 193g of 2-propanol, and the slurry warmed to a gentle reflux with a jackettemperature of 85° C. to give a solution. The solution was sampled forHPLC analysis; the results are listed in FIG. 13. A slurry formed uponcooling to 65° C. After warming to 68° C. for 30 min, the slurry wascooled to 40° C. at 0.25° C./min, then to 18° C. at 0.4° C./min, then to2° C. at 1° C./min. (In other preparations, linear cooling ratesrecorded in FIG. 14 were used.) The solid was isolated by vacuumfiltration, rinsed with 18 g of 2-propanol, and dried under vacuum togive 27.29 g (50.4 mmol, 34.5% yield) of (−)-CPTA/CAF D-Base. HPLCanalysis results for the isolated solid and mother liquor and wash areincluded in FIG. 13.

Example 35

This example illustrates preparation and resolution of racemic CPTA fromhalofenate.

A 1-L round-bottom flask with an overhead stirrer was charged with129.75 g (0.312 mol) of racemic halofenate, 325 g of water, and 32.6 g(0.408 mol) of 50% aqueous sodium hydroxide. The slurry was heated to60° C. for 1 hour to give a solution, then cooled. At a temperature of40° C., 328.5 g of 1,2-dichloroethane and 44 g (0.45 mol) of 37%hydrochloric acid were added, and the two-phase mixture was cooled to29° C. The pH of the aqueous phase was 0.85. The organic phase wasseparated and washed with 250 mL of water, then evaporated to a residueof 118.2 g. 2-Propanol (149 g) was added, and evaporated to a residue of131.2 g. The residue, containing theoretically 103.2 g of racemic CPTAbased on the amount of halofenate loaded, was charged to a 1-Lbottom-drain reactor with 33.10 g (0.1556 mol) of CAF D-Base and 400 gof 2-propanol. The mixture was warmed to 67° C. to give a light slurry,then cooled to 1° C. at 0.075° C./min. The mixture was chilled to −7°C., and the solid isolated by vacuum filtration and washed with 60 mL of2-propanol. HPLC analysis results of the isolated solid and the 492.8-gmother liquor and wash solution are shown in FIG. 13 (experiment 9). The92.74-g wetcake was reloaded to the 1-L reactor along with 477 g of2-propanol, and the mixture heated to 75° C. to give a solution. Thesolution was cooled to 5° C. at 0.5° C./min, and the crystallized solidisolated by vacuum filtration, rinsed with 60 mL of 2-propanol, anddried to give 51.81 g (0.0956 mol, 31% yield) of the (−)-CPTA CAF D-Basediastereomeric salt. HPLC analysis results for the isolated solid and529.9 g of mother liquor and wash solution are included in FIG. 13.

Example 36

This example illustrates a method for racemizing (+)-CPTA and recoveringracemic CPTA.

The resolution and recrystallization mother liquors from the resolutionof 103.2 g of CPTA described in Example 35 above, containing 71.6 g(0.217 mol) of CPTA (44% ee of the (+)-enantiomer) based on the yieldand purity of the isolated diastereomeric salt, was evaporated to aresidue of 108.7 g. The residue was treated with 176 g of1,2-dichloroethane, 35.2 g of water, and 6.8 g of 37% hydrochloric acid.The organic phase was removed and evaporated to a residue to 79.0 g.Water (80 g) was added, and the solvent evaporated to a residue of 78.1g. The residue was treated with 141.9 g of water and 24.6 g (0.308 mol)of 50% aqueous sodium hydroxide, and the solution was heated to refluxfor 4 hours to give a racemate by chiral HPLC analysis. The solution wascooled and treated with 140 ml, of 1,2-dichloroethane and 32.0 g (0.325mol) of 37% hydrochloric acid. The organic phase was removed andevaporated to a residue of 80.1 g, which was treated with 250 mL ofheptane in a 40° C. water bath to give a slurry. The solid was isolatedby vacuum filtration and dried to give 63.83 g (0.193 mol, 89% yield) ofracemic CPTA. Resolution of a sample gave results consistent with thoseof fresh CPTA (entry 10 of FIG. 13).

Example 37

This example illustrates a method for isolating (−)-CPTA from thediastereomeric salt.

A 500-mL flask with a magnetic stirrer was charged with 40.0 g (73.7mmol) of (−)-CPTA/CAF D-Base, 100 g of 1,2-dichloroethane, 40 g of waterand 7.6 g (77 mmol) of 37% hydrochloric acid. After complete dissolutionof the solid, the lower organic phase was removed and washed with 10 mLof water. The pH of the combined aqueous phase was 0.9.

HPLC assay of 128.2 g of the organic phase found 24.32 g (73.6 mmol,99.8% of theory) of (−)-CPTA as a solution in 1,2-dichloroethane.

Example 38

This example illustrates a vacuum purification of N-acetylethanolamine.

A 50-mL round-bottom flask equipped with a magnetic stirrer, heatingmantel and a short path distillation head was charged with 29.09 g ofN-acetylethanolamine and placed under a vacuum of approximately 0.8torr. Bubbles formed as the liquid was heated, although no condensatewas collected. Distillate was collected at a head temperature ofapproximately 130° C. to afford 26.71 g (92% recovery) ofN-acetylethanolamine as a clear liquid.

Example 39

This example illustrates a method for producing (−)-halofenate.

A 500-mL round-bottom flask with a magnetic stirrer was charged with35.5 g (65.4 mmol) of the (−)-CPTA/CAF D-Base diastereomeric salt (99.4%ee), 89.0 g of 1,2-dichloroethane, and 35.5 mL of water. To the slurrywas added 6.7 g (68 mmol) of 37% hydrochloric acid, and the mixture wasstirred at ambient temperature to give two clear phases. The lowerorganic phase was removed and washed with 7.0 g of water. The organicphase was evaporated to a residue of 26.13 g, then dissolved in 55.6 gof 1,2-dichloroethane and placed in a 250-mL round-bottom flask in aheating mantel with a magnetic stirrer and fitted with areflux/distillation head. HPLC assay of the solution found 22.06 g (66.7mmol, 102% of theory) of CPTA. To the solution was added 7.5 mL (100mmol) of thionyl chloride, and the solution was heated to reflux for 2hours. Heating was continued to collect 6.1 g of distillate. Thesolution was cooled to ambient temperature, then chilled in an ice bathfor the addition of 25.85 g (251 mmol) of distilled N-acetylethanolamine(KF analysis 1176 and 1288 ppm water). The temperature rose to about 26°C. after the addition. The solution was added slowly with stirring to9.90 g (71.6 mmol) of potassium carbonate in 36 g of water chilled in anice bath. The maximum temperature reached was 15° C. The reactionmixture was rinsed in with 5 mL of 1,2-dichloroethane. The lower organicphase was removed and washed with 37 mL of water. The solution wasevaporated to give an oil (32.84 g). The oil was treated with 54 g ofheptane, and the solvent was removed to give 31.56 g of a solid residue.To the solid was added 76 g of heptane, and the solvent was removed togive 29.19 of a solid residue. The solid was dissolved in 28 mL of2-propanol at 40° C., then diluted with an additional 28 mL of 20propanol and 334 mL of heptane. Cooling to ambient temperature gave athin slurry. A thick slurry formed upon cooling in an ice bath. Afterstirring for 2 hours, the solid was isolated by vacuum filtration,rinsed with 29 g of heptane, and dried to give 14.21 g (34.2 mmol, 52.3%yield) of (−)-halofenate. No (+)-halofenate was detected by chiral HPLCanalysis (>99.8% ee).

HPLC assay of 294.1 g of the mother liquor and wash found 11.2 g ofhalofenate and 1.26 g of CPTA. The solvent was evaporated, and 12.47 gof the residue was dissolved in 14 mL of 2-propanol. Addition of 84 mLof heptane gave a slurry after stirring overnight at ambienttemperature. The slurry was chilled in an ice bath and the solid wascollected, rinsed with 9 g of heptane, and dried to give 5.64 g (13.6mmol, 20.7% yield, 89.9% halofenate and 3.9% CPTA by HPLC analysis,99.6% ee) of (−)-halofenate. HPLC assay of 81.74 g of the mother liquorand wash found 3.66 g (8.8 mmol, 13.5%) of halofenate and 0.93 g (2.8mmol, 4.8%) of CPTA.

Example 40

This example illustrates a method for isolating racemic CPTA sodiumsalt.

The mother liquors from a resolution crystallization andrecrystallization containing in theory 63.9 g (0.193 mol) of CPTA basedon the resolution recovery was evaporated to a residue of 91 g. Theresidue was dissolved in 146 g of 1,2-dichloroethane and treated with28.6 g of water and 6.3 g of 37% hydrochloric acid at 40° C. The 219 gorganic phase was evaporated to a residue of 71.86 g. To the residue wasadded 120 g of water and 21.5 g (0.269 mol) of 50% sodium hydroxide. Thesolution was heated to reflux, then allowed to cool to ambienttemperature to give a thick slurry. The solid that formed upon coolingwas isolated by vacuum filtration, rinsed with 25 mL of water, thendried to give 31.78 g (0.0901 mol, 46.7% recovery) of the sodium salt ofCPTA. Chiral HPLC analysis found that the material was racemic. HPLCassay of the 188.6 g mother liquor and wash found 28.3 g (0.0856 mol,44.4%) of CPTA.

Example 41

This example illustrates a method for determining the solubility ofracemic CPTA sodium salt.

A 100-mL water jacketed resin pot with a magnetic stirrer was connectedto a recirculating water bath and charged with 3.48 g of the racemicCPTA sodium salt and 20.0 g of water. The bath temperature was warmed to35° C., and the slurry was stirred for one hour. The agitator was shutoff, and the solid was allowed to settle for 30 min. The pH was 9.4. A0.3036 g-sample of the supernate was removed and diluted to 25.00 mLwith acetonitrile, and the solution was assayed by HPLC analysis.Analysis was repeated at 47° C. and at 19° C. An additional 3.01 g ofCPTA sodium salt was added to maintain a slurry at the highertemperature, and 25 g of water was added to give a thinner slurry at thelower temperature. The pH was increased to 12.7 at ambient temperatureby the addition of 50% aqueous sodium hydroxide, and the analysis wascontinued at 13.5, 25, 34, and 42° C. Results are shown in FIGS. 16 and20.

Example 42

This example illustrates hydrolysis and racemization of (+)-halofenate.

A 250-mL round-bottom flask equipped with a magnetic stirrer and heatingmantel was charged with 7.28 g (17.5 mmol) of (+)-halofenate (86.9% ee),72.2 g of water, and 4.21 g (52.6 mmol) of 50% aqueous sodium hydroxide.The slurry was heated to 50 to 60° C. The pH of the resulting solutionwas 12.8. Chiral HPLC analysis showed 80.4% of (+)-CPTA and 10.5% of(−)-CPTA. The solution was heated to reflux for 90 minutes. Chiral HPLCanalysis showed 49.6% of (+)-CPTA and 47.0% of (−)-CPTA. The pH was12.6. After cooling to ambient temperature, approximately 50 mL of1,2-dichloroethane was added, and the pH was adjusted to 0.8 by theaddition of 7.3 g (74 mmol) of 37% hydrochloric acid. The organic phasewas evaporated to a residue of 6.0 g. The residue was treated with 25 mLof heptane, warmed to dissolve the oil, and then cooled in an ice bath.The solid was collected by vacuum filtration and dried to give 5.10 g(15.4 mmol, 88% yield) of racemic CPTA. Data for this and two similarhydrolyses are shown in FIGS. 17 and 21.

Similarly, heating 6.75 g (16.3 mmol) of (+)-halofenate with 0.65 g (8.1mmol) of 50% aqueous sodium hydroxide in 67.5 g of water for 2 hours at60° C. gave 37.5% of halofenate and 54.2% of CPTA. Heating to refluxovernight gave 92.1% of CPTA and 1.1% of halofenate, with a final pH of4.8. Chiral HPLC analysis found an 80.3/12.8 ratio of (+)/(−)-CPTA.

Example 43

This example illustrates preparation of (−)-halofenate with recovery ofthe (−)-CPTA/CAF D-Base diastereomeric salt from the (−)-halofenatecrystallization mother liquors.

A 1-L round bottom flask with magnetic stirring was charged with 50.0 g(92.3 mmol) of the (−)-CPTA/CAF D-Base diastereomeric salt (97.1% ee),124 g of 1,2-dichloroethane, 50 mL of water, and 9.6 g (98 mmol) of 37%hydrochloric acid. The organic phase was separated and washed with 50 mLof water, then placed in a 250-mL round-bottom flask in a heating mantelwith a magnetic stirrer. A reflux/distillation head was attached, andthe solution was heated to remove 35.4 g of distillate by distillation.After cooling to 40° C., the solution was diluted with 25 mL of1,2-dichloroethane, and 11 mL (150 mmol) of thionyl chloride was added.After heating at reflux for 2 hours and removing 22.6 g of distillate,the solution was cooled in an ice bath for the dropwise addition of 38.6g (374 mmol) of distilled N-acetylethanolamine. The reaction temperaturerose from 7 to 18° C. during the addition. After stirring overnight atambient temperature, the solution was added with stirring to 12.7 g ofpotassium carbonate in 51 mL of water chilled in an ice bath. Theorganic phase was removed and washed with 51 g of water. The organicphase (85.2% of halofenate and 6.1% CPTA by HPLC analysis) wasevaporated to an oil of 44.3 g, treated with 133 g of heptane, thenevaporated to a solid of 43.3 g. The solid residue was dissolved in 61.5g of 2-propanol and charged to the 1-L bottom-drain reactor along with320 g of heptane, warmed to 50° C., and cooled at 3° C./min to 20° C.,then at 1° C./min to −3° C. The solution became hazy at 27° C., and athick slurry formed at 15° C. The solid was isolated by vacuumfiltration, washed with 40 mL of heptane containing 5 mL of 2-propanol,and dried to give 21.01 g (50.6 mmol. 55% yield, 98.93% by HPLC) of(−)-halofenate (99.9% ee). The 395.7 g mother liquor and wash solution,containing 14.65 g (35.3 mmol) of halofenate (88.3% ee) and 1.78 g (5.4mmol) of CPTA by HPLC assay, was evaporated to a residue of 21.57 g. Theresidue was heated to 50° C. with 100 mL of water and 5.0 g (63 mmol) of50% aqueous sodium hydroxide to give a solution. HPLC analysis afterabout 10 minutes found 83.6% of CPTA and 0.3% of halofenate. Thesolution was cooled, diluted with 50 mL of 1,2-dichloroethane, and thepH decreased from 12.7 to 1.6 with 7.3 g (74 mmol) of 37% hydrochloricacid. After washing with 30 mL of water, the 72.9 g organic phase,containing 11.32 g (34.2 mmol) of CPTA by HPLC assay, was evaporated toa residue, treated with 36 g of heptane, then evaporated to a residue of14.9 g. The oily residue was dissolved in 38 g of heptane with heating.Cooling gave an oil. The solvent was removed and the residual oildissolved in 34.8 g of methylcyclohexane. An oil formed with cooling.The solvent was removed and replaced with 45.6 g of 2-propanol. ChiralHPLC analysis found 65.8% ee of (−5)-CPTA (a (+)/(−)-ratio of16.9/81.6). To the solution at ambient temperature was added 6.50 g(30.6 mmol) of CAF D-Base. A thick slurry rapidly formed. The slurry waswarmed to 40° C. with stirring, then cooled in an ice bath and the solidisolated by a vacuum filtration, washed with 7 g of 2-propanol, anddried to give 13.91 g (25.7 mmol) of (−)-CPTA/CAF D-Base diastereomericsalt, which corresponds to 28% recovery of the 50.0 g of salt initiallyloaded. The (+)/(−)-CPTA ratio was 1.77/97.86. HPLC assay of the 45.34-gmother liquor and wash solution found 4.34 g (13.1 mmol) of CPTA, whichcorresponds to 14 mol % of the 50.0 g of salt initially loaded.

Example 44

This example illustrates a process for recovering CAF D-Base fromCPTA/CAF D-Base salt.

A 1-L round-bottom flask with a magnetic stirrer was charged with 80.16g (0.148 mol) of the (−)-CPTA/CAF D-Base salt, 237 g of1,2-dichloroethane, and 80 mL of water. To the slurry was added 15.2 g(0.154 mol) of 37% hydrochloric acid, giving two clear phases. The pH ofthe aqueous layer was 1.2. The lower organic layer was removed andwashed with 16 mL of water. The combined aqueous phase (140.7 g) wastreated with 12.9 g (0.161 mol) of 50% aqueous sodium hydroxide to reacha pH of 12.1. The resulting slurry was filtered and the solid was rinsedwith 25 mL of water and dried to give 30.79 g (0.145 mol, 98% recovery)of CAF D-Base (mp 160.4-161.0° C.).

Example 45

This example illustrates a process for recovering CAF D-Base from theresolution mother liquor.

A 60.0 g sample of racemic CPTA was resolved with 20.88 g of CAF D-Basein 240 g of 2-propanol as described above to give a 74.7 g wetcake. Thewetcake was recrystallized in 218 g of 2-propanol to give 32.35 g (32.8%yield) of (−)-CPTA/CAF D-Base salt. The mother liquor and wash solutionsfrom the crystallization and recrystallization, theoretically containing40.32 g of CPTA and 8.23 g (38.8 mmol) of CAF D-Base from the amount ofsalt obtained, was evaporated to a residue of 72.9 g. The residue wasdissolved in 265 g of 1,2-dichloroethane, 50 mL of water, and 4.0 g(40.6 mmol) of 37% hydrochloric acid. The aqueous layer was separated,and the pH was increased from 0.6 to 12.3 by the addition of 3.88 g(48.5 mmol) of 50% aqueous sodium hydroxide. The resulting slurry wasfiltered and the solid was collected and rinsed with water to give 7.12g (33.6 mmol, 87% recovery) of CAF D-Base (mp 162.4-163.0° C.).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A method for resolving an enantiomerically enrichedα-(phenoxy)phenylactic acid compound of the formula:

wherein R¹ is alkyl or haloalkyl, and X is halide; from an enantiomericmixture of the α-(phenoxy)phenylactic acid compound comprising a firstand a second enantiomers, said method comprising: (a) contacting theenantiomeric mixture of the α-(phenoxy)phenylactic acid compound withless than 0.5 molar equivalents of an enantiomerically enriched chiralamine compound with respect to the α-(phenoxy)phenylactic acid compoundand (b) separating the solid acid-base salt of the first enantiomer fromthe second enantiomer of the α-(phenoxy)phenylactic acid compound. 2.The method of claim 24, wherein said step (i) of producing thecrystallization solution comprising the solid enantiomerically enrichedacid-base salt of the first enantiomer comprises: (i1) heating thesolution mixture to a temperature above the nucleation temperature ofthe first enantiomer; and (i2) lowering the solution mixture temperatureto a temperature at or below the nucleation temperature of the firstenantiomer to produce the solid acid-base salt of the first enantiomer.3. The method of claim 2, wherein said step (ii) of separating the solidacid-base salt of the first enantiomer is conducted at a temperaturenear or above a saturation temperature of an acid-base salt of thesecond enantiomer.
 4. The method of claim 1 further comprisingrecovering the chiral amine compound by removing the chiral aminecompound from the separated solid acid-base salt of the firstenantiomer.
 5. The method of claim 4, wherein the enantiomericallyenriched chiral amine compound used in producing the acid-base salt ofsaid step (a) comprises the recovered chiral amine compound.
 6. Themethod of claim 1 further comprising racemizing at least a portion ofthe second enantiomer in the separated solution mixture by contactingthe second enantiomer with a base.
 7. The method of claim 6, wherein theenantiomeric mixture of the α-(phenoxy)phenylactic acid compound used insaid step (a) comprises a racemized α-(phenoxy)phenylactic acidcompound.
 8. The method of claim 1, wherein the chiral amine compound isof the formula:

wherein each of R² and R³ is independently hydrogen or alkyl; or R² andR³ together with atoms to which they are attached to form a heterocyclicring moiety; R⁴ is hydrogen or alkyl; each of R⁵ and R⁶ is independentlyhydrogen or alkyl, or one of R⁵ or R⁶ is an amine protecting group; andAr is aryl.
 9. The method of claim 1, wherein the α-(phenoxy)phenylacticacid is an enantiomeric mixture of4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid, said methodcomprising: (a) producing a crystallization solution mixture comprisingan enantiomerically enriched acid-base salt of(−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid by contactingthe enantiomeric mixture of4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid with less than 0.5molar equivalent of an enantiomerically enriched(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol in about 4 grams of analcoholic solvent per gram of(−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid; (b)separating the enantiomerically enriched acid-base salt from thesolution mixture which is enriched with(+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid; and (c)removing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol from theacid-base salt to produce enantiomerically enriched(−)-4-chloro-α-(3-trifluoromethyl-phenoxy)phenylactic acid.
 10. Themethod of claim 9, wherein the alcoholic solvent is isopropanol.
 11. Themethod of claim 10, wherein about 0.47 molar equivalent or less of(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol is used to form theacid-base salt.
 12. The method of claim 11, wherein said step (a) ofproducing a solution comprising an enantiomerically enriched acid-basesalt of (−)-4-chloro-α-(3-trifluoromethyl-phenoxy)phenylactic acidcomprises heating the solution mixture to a temperature at or above anucleation temperature of the (−)-acid-base salt.
 13. The method ofclaim 12, wherein said step (b) of separating the enantiomericallyenriched acid-base salt is performed at a temperature near or above asaturation temperature of an acid-base salt of the (+)-enantiomer. 14.The method of claim 10, wherein the enantiomerically enriched(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol comprises at least aportion of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol that isremoved from the acid-base salt of said step (c).
 15. The method ofclaim 10 further comprising racemizing at least a portion of(+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid obtained insaid step (b).
 16. The method of claim 15, wherein the enantiomericmixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acidcomprises at least a portion of(+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid that isracemized.
 17. An acid-base salt derived from the method of claim
 1. 18.The acid-base salt of claim 17, wherein the α-(phenoxy)phenylactic acidcompound and the chiral amine compound are enantiomerically enriched.19. The acid-base salt of claim 18, wherein the α-(phenoxy)phenylacticacid compound is (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacticacid.
 20. The acid-base salt of claim 18, wherein the chiral aminecompound is (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.
 21. Theacid-base salt of claim 19 having an enantiomeric excess of at leastabout 95%.
 22. (canceled)
 23. (canceled)
 24. The method of claim 1,wherein said step (a) comprises: (i) producing a crystallizationsolution mixture comprising a solid enantiomerically enriched acid-basesalt of a first enantiomer by contacting the enantiomeric mixture of theα-(phenoxy)phenylactic acid compound with the enantiomerically enrichedchiral amine compound under conditions sufficient to produce the ratioof the amount of first enantiomer to the amount of the second enantiomerin the salt is at least about 3:1, wherein the total amount ofenantiomerically enriched chiral amine compound used is less than 0.5molar equivalents with respect to the α-(phenoxy)phenylactic acidcompound and (b) separating the solid acid-base salt of the firstenantiomer from the solution mixture at a temperature where theconcentration of an acid-base salt of the second enantiomer of theα-(phenoxy)phenylactic acid compound is near or below its saturationpoint.